Hereditary Colorectal Cancers

Currently, two types of hereditary CRCs are well-defined: familial adenomatous polyposis (FAP) and Lynch syndrome (formerly hereditary nonpolyposis CRC). Lynch syndrome has been implicated in some endometrial cancers as well.

FAP and Associated Variants

FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will develop CRC. Mean age of colon cancer diagnosis in untreated individuals is 39 years. FAP accounts for about 1% of CRC and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina referred to as congenital hypertrophy of the retinal pigment epithelium. FAP associated with these collective extraintestinal manifestations is sometimes referred to as Gardner syndrome. FAP may also be related to central nervous system tumors, referred to as Turcot syndrome.

Germline variants in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Variants in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene variant (I1307K) has been found in Ashkenazi Jewish descendants, which may explain a portion of the familial CRC occurring in this population.

A subset of FAP patients may have an attenuated form of FAP, typically characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP. In the attenuated form of FAP, CRC occurs later in life (at an average age of 50 to 55 years) but lifetime risk of CRC remains high (»70% by age 80 years). The risk of extraintestinal cancer is also lower but cumulative lifetime risk remains high (»38%) compared with the general population.^1, Only 30% or fewer of attenuated FAP patients have APC variants; some of these patients have variants in the MUTYH (formerly MYH) gene, and this form of the condition is called MUTYH-associated polyposis (MAP). MAP occurs with a frequency similar to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or attenuated FAP, a strong multigenerational family history of polyposis is absent. Biallelic MUTYH variants are associated with a cumulative CRC risk of about 80% by age 70, whereas the monoallelic MUTYH variant-associated risk of CRC appears to be relatively minimal, although still under debate.^2, Thus, inheritance for high-risk CRC predisposition is autosomal recessive in contrast to FAP. When relatively few (ie, between 10 and 99) adenomas are present, and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MUTYH if APC is negative for variants, and screening for variants associated with Lynch syndrome.

It is important to distinguish among classical FAP, attenuated FAP, and MAP (mono- or biallelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary by syndrome.^3,

Testing

Genetic testing for APC variants may be considered in the following situations:

• Patients at high-risk such as those with a family member who tested positive for FAP and have a known APC variant.
• Patients undergoing differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome. These patients do not meet the clinical diagnostic criteria for classical FAP and have few adenomatous colonic polyps.
• To confirm FAP in patients with colon cancer with a clinical picture or family history consistent with classical FAP.

Lynch syndrome is an inherited disorder that results in a higher predisposition to CRC and other malignancies including endometrial and gastric cancer. Lynch syndrome is estimated to account for 3% to 5% of all CRC. People with Lynch syndrome have a 70% to 80% lifetime risk of developing any type of cancer.^4,5, However the risk varies by genotype. It occurs as a result of germline variant in the mismatch repair (MMR) genes that include MLH1, MSH2, MSH6, and PMS2. In approximately 80% of cases, the variants are located in the MLH1 and MSH2 genes, while 10% to 12% of variants are located in the MSH6 gene and 2% to 3% in the PMS2 gene. Additionally, variants in three additional genes (MLH3, PMS1, EX01) have been implicated with Lynch Syndrome. Notably, in individuals meeting the various clinical criteria for Lynch syndrome, 50% of individuals have a variant in the MLH1, MSH2, MSH6, and PMS2 genes. The lifetime risk of CRC is nearly 80% in individuals carrying a variant in 1 of these genes.

Testing

Testing approach to identify patients with Lynch syndrome is summarized next. Preliminary screening of tumor tissue does not identify MMR gene variants but is used to guide subsequent diagnostic testing via DNA analysis for specific variants. Genetic testing or DNA analysis (gene sequencing, deletion, and duplication testing) for the MMR genes involves assessment for MLH1, MSH2, MSH6, and PMS2 variants. The following are three testing strategies.

1. Microsatellite instability (MSI) testing (phenotype): Individuals with high MSI either proceed to genetic testing for MLH1, MSH2, MSH6, and PMS2 or to immunohistochemical (IHC) testing.
2. IHC testing (phenotype): Individuals with negative staining would proceed to genetic testing for MLH1, MSH2, MSH6, and PMS2.
3. Modification strategy: Tumor tissue of patients with negative staining for MLH1 on IHC is tested for the BRAF V600E variant to determine methylation status. If the BRAF variant is not detected, the individual receives MLH1 DNA analysis.

The second phenotype screening test is IHC, which involves the staining of tumor tissue for the presence of four MMR proteins (MLH1, MSH2, MSH6, PMS2). The absence of one or more of these proteins is considered abnormal.

BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency. A methylation analysis of the MLH1 gene can largely substitute for BRAF testing, or be used in combination to improve efficiency slightly.

Both MSI and IHC have a 5% to 10% false-negative rate. MSI testing performance depends on the specific MMR variant. MSI screening has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6 and a specificity of about 90% for each. The specificity of MSI testing is low because approximately 10% of sporadic CRCs are MSI-positive due to somatic hypermethylation of the MLH1 promoter. Additionally, some tumors positive for MSH6 variants are associated with the MSI-low phenotype rather than MSI-high; thus MSI-low should not be a criterion against proceeding to MMR variant testing.^7,8, IHC screening has sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for each.

Screening of tumor tissue from patients enables genetic testing for a definitive diagnosis of Lynch syndrome and leads to counseling, cancer surveillance (eg, through frequent colonoscopic or endometrial screening examinations), and prophylaxis (eg, risk-reducing colorectal or gynecologic surgeries) for CRC patients, as well as for their family members.

Genetic testing for an MMR gene variant is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2. The BRAF gene is often mutated in CRC when a particular BRAF variant (V600E, a change from valine to glutamic acid at amino acid position 600 in the BRAF protein) is present; to date, no MLH1 gene variants have been reported.^9, Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 variant, could first be screened for a BRAF variant. BRAF-positive samples need not be further tested by MLH1 sequencing. MLH1 gene methylation largely correlates with the presence of BRAF V600E and in combination with BRAF testing can accurately separate Lynch from sporadic CRC in IHC MLH1-negative cases.^10,

Recently, novel deletions have been reported to affect the expression of the MSH2 gene in the absence of an MSH2 gene variant, and thereby cause Lynch syndrome. In these cases, deletions in EPCAM, the gene for the epithelial cell adhesion molecule, are responsible. EPCAM testing has been added to many Lynch syndrome profiles and is conducted only when tumor tissue screening results are MSI-high and/or IHC shows a lack of MSH2 expression, but no MSH2 variant is found by sequencing. EPCAM is found just upstream, in a transcriptional sense, of MSH2. Deletions of EPCAM that encompass the last two exons of the EPCAM gene, including the polyadenylation signal that normally ends transcription of DNA into messenger RNA, results in transcriptional “read-through” and subsequent hypermethylation of the nearby and downstream MSH2 promoter. This hypermethylation prevents normal MSH2 protein expression and leads to Lynch syndrome in a fashion similar to Lynch cases in which an MSH2 variant prevents MSH2 gene expression. Several studies have characterized such EPCAM deletions, established their correlation with the presence of EPCAM-MSH2 fusion messenger RNAs (apparently nonfunctional) and with the presence of MSH2 promoter hypermethylation, and, most importantly, have shown the cosegregation of these EPCAM variants with Lynch-like disease in families.^{11,12,13,14,15,16,}

Distinct from patients with EPCAM deletions, rare cases of Lynch syndrome have been reported without detectable germline MMR variants, although IHC testing demonstrated a loss of expression of one of the MMR proteins. In at least some of these cases, research has identified germline “epivariants,” ie, methylation of promoter regions that control the expression of the MMR genes.^11,17,18, Such methylation may be isolated or be in conjunction with a linked genetic alteration near the affected MMR gene. The germline epivariants may arise de novo or may be heritable in Mendelian or non-Mendelian fashion. This is distinct from some cases of MSI-high sporadic CRC wherein the tumor tissue may show MLH1 promoter methylation and IHC nonexpression, but the same is not true of germline cells. Clinical testing for Lynch syndrome-related germline epivariants is not routine but may help in exceptional cases.

Female patients with Lynch syndrome have a predisposition to endometrial cancer. Lynch syndrome is estimated to account for 2% of all endometrial cancers in women and 10% of endometrial cancers in women younger than 50 years of age. Female carriers of the germline variants MLH1, MSH2, MSH6, and PMS2 have an estimated 40% to 62% lifetime risk of developing endometrial cancer, as well as a 4% to 12% lifetime risk of ovarian cancer.

Population Selection

Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR variants, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria^19, (low sensitivity but high specificity), Revised Bethesda guidelines^20, (better sensitivity but poorer specificity), and risk prediction models (eg, MMRpro; PREMM5; MMRpredict).^21, While family history is an important risk factor and should not be discounted in counseling families, it has poor sensitivity and specificity for identifying Lynch syndrome. Based on this and other evidence, the Evaluation of Genomic Applications in Practice and Prevention Working Group recommended testing all newly diagnosed CRC patients for Lynch syndrome, using a screening strategy based on MSI or IHC (with or without BRAF) followed by sequencing in screen-positive patients. This recommendation includes genetic testing for the following types of patients:

• Family members of Lynch syndrome patients with a known MMR variant; family members would be tested only for the family variant; those testing positive would benefit from early and increased surveillance to prevent future CRC.
• Patients with a differential diagnosis of Lynch syndrome vs attenuated FAP vs MAP.
• For Lynch syndrome patients, genetic testing of the proband with CRC likely benefits the proband where Lynch syndrome is identified, and appropriate surveillance for associated malignancies can be initiated and maintained and benefits family members by identifying the family variant.

JPS is an autosomal dominant genetic disorder characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract. It is rare, with an estimated incidence of 1 in 100000 to 160000. Generalized JPS refers to polyps in the upper and lower gastrointestinal tract, and juvenile polyposis coli refers to polyps of the colon and rectum. Those with JPS are at a higher risk for CRC and gastric cancer.^22, Approximately 60% of patients with JPS have a germline variant in the BMPR1A gene or the SMAD4 gene.^23,24, Approximately 25% of patients have de novo variants.^25,26, In most cases, polyps appear in the first decade of life and most patients are symptomatic by age 20 years.^27, Rectal bleeding is the most common presenting symptom, occurring in more than half of patients. Other presenting symptoms include prolapsing polyp, melena, pain, iron deficiency anemia, and diarrhea.^22,26,27,

As noted, individuals with JPS are at increased risk for CRC and gastric cancer. By 35 years of age, the cumulative risk of CRC is 17% to 22%, which increases to 68% by age 60 years.^28,29, The estimated lifetime risk of gastric cancer is 20% to 30%, with a mean age at diagnosis of 58 years.^22,26,28, JPS may also be associated with hereditary hemorrhagic telangiectasia.^30, The most common clinical manifestations of hereditary hemorrhagic telangiectasia are telangiectasias of the skin and buccal mucosa, epistaxis, and iron deficiency anemia from bleeding.

Diagnosis

A clinical diagnosis of JPS is made on the basis of the presence of any one of the following: at least threeto five juvenile polyps in the colon or multiple juvenile polyps in other parts of the gastrointestinal tract or any number of juvenile polyps in a person with a known family history of juvenile polyps.^31, It is recommended that individuals who meet clinical criteria for JPS undergo genetic testing for a germline variant in the BMPR1A and SMAD4 genes for a confirmatory diagnosis of JPS and to counsel at-risk family members. If there is a known SMAD4 variant in the family, genetic testing should be performed within the first six months of life due to hereditary hemorrhagic telangiectasia risk.^31,

Peutz-Jeghers Syndrome

PJS is also an autosomal dominant genetic disorder, similar to JPS, and characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract, mucocutaneous pigmentation, and an increased risk of gastrointestinal and nongastrointestinal cancers. It is rare, with an estimated incidence of 1 in 8000 to 200000. In most cases, a germline variant in the STK11 (LKB1) gene is responsible for PJS, which has a high penetrance of over 90% by the age of 30 years.^32,33,34, However, 10% to 20% of individuals with PJS have no family history and are presumed to have PJS due to de novo variants.^35,A variant in STK11is detected in only 50% to 80% of families with PJS, suggesting that there is a second PJS gene locus.

The reported lifetime risk for any cancer is between 37% and 93% among those diagnosed with PJS with an average age of cancer diagnosis at 42 years. The most common sites for malignancy are colon and rectum, followed by breast, stomach, small bowel, and pancreas.^36, The estimated lifetime risk of gastrointestinal cancer ranges from 38% to 66%.^36, Lifetime cancer risk stratified by organ site is colon and rectum (39%), stomach (29%), small bowel (13%), and pancreas (11%-36%).

Diagnosis

A clinical diagnosis of PJS is made if an individual meets two or more of the following criteria: presence of two or more histologically confirmed PJ polyps of the small intestine or characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, fingers, or family history of PJS.^31, Individuals who meet clinical criteria for PJS should undergo genetic testing for a germline variant in the STK11 gene for a confirmatory diagnosis of PJS and counseling at-risk family members.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests reviewed in this policy are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

Related Policies

• None

For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

I. Genetic testing for APC gene variants is considered medically necessary in the following members:

• At-risk relatives (see Policy Guidelines section) of members with familial adenomatous polyposis (FAP) and/or a known APC variant.
• Members with a differential diagnosis of attenuated FAP versus MUTYH-associated polyposis (MAP) versus Lynch syndrome. Whether testing begins with APC variants or screening for mismatch repair (MMR) variants depends upon clinical presentation.

• Members with a differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome AND a negative result for APC gene variants. A family history of no parents or children with FAP is consistent with MAP (autosomal recessive).
  

• Members with colorectal cancer (CRC), for the diagnosis of Lynch syndrome (see Policy Guidelines section).
• Members with endometrial cancer and a first-degree relative diagnosed with a Lynch-associated cancer (see Policy Guidelines section), for the diagnosis of Lynch syndrome.
• At-risk relatives (see Policy Guidelines section) of members with Lynch syndrome with a known MMR gene variant.
  
• Members with a differential diagnosis of attenuated FAP versus MAP versus Lynch syndrome. Whether testing begins with APC variants or screening for MMR genes depends on clinical presentation.
• Members without CRC but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g., MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants.

• Members with CRC, for the diagnosis of Lynch syndrome (see Policy Guidelines section) when:
  • Tumor tissue shows lack of MSH2 protein expression by immunohistochemistry and member is negative for a MSH2 germline variant; or
  • Tumor tissue shows a high level of microsatellite instability and member is negative for a germline variant in MSH2, MLH1, PMS2, and MSH6; OR
• At-risk relatives (see Policy Guidelines section) of members with Lynch syndrome with a known EPCAM variant; OR
  
• Members without CRC but with a family history meeting the Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model (e.g., MMRpro, PREMM5 or MMRpredict), when no affected family members have been tested for MMR variants, and when sequencing for MMR variants is negative.

• Members with a clinical diagnosis of juvenile polyposis syndrome based on the presence of any one of the following:
  o at least 3 to 5 juvenile polyps in the colon
  o multiple juvenile polyps in other parts of the gastrointestinal tract
  o any number of juvenile polyps in a person with a known family history of juvenile polyps.
• At-risk relative of a member suspected of or diagnosed with juvenile polyposis syndrome.

• Members with a clinical diagnosis of Peutz-Jeghers syndrome based on the presence of any 2 of the following:
  o presence of 2 or more histologically confirmed Peutz-Jeghers polyps of the small intestine
  o characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers
  o family history of Peutz-Jeghers syndrome.
• At-risk relative of a member suspected of or diagnosed with Peutz-Jeghers syndrome.

Testing At-Risk Relatives
Due to the high lifetime risk of cancer of most genetic syndromes discussed in this policy, “at-risk relatives” primarily refers to first-degree relatives. However, some judgment must be permitted, eg, in the case of a small family pedigree, when extended family members may need to be included in the testing strategy.

Targeted Familial Variant Testing
It is recommended that, when possible, initial genetic testing for familial adenomatous polyposis or Lynch syndrome be performed in an affected family member so that testing in unaffected family members can focus on the variant found in the affected family member (see Benefit Application section).

In many cases, genetic testing for MUTYH gene variants should first target the specific variants Y165C and G382D, which account for more than 80% of variants in white populations, and subsequently proceed to sequence only as necessary. However, in other ethnic populations, proceeding directly to sequencing is appropriate.

Evaluation for Lynch Syndrome
For patients with colorectal cancer (CRC) being evaluated for Lynch syndrome, either the microsatellite instability (MSI) test or the immunohistochemical (IHC) test with or without BRAF gene variant testing, should be used as an initial evaluation of tumor tissue before mismatch repair (MMR) gene analysis. Both tests are not necessary. Proceeding to MMR gene sequencing would depend on results of MSI or IHC testing. In particular, IHC testing may help direct which MMR gene likely contains a variant, if any, and may also provide additional information if MMR genetic testing is inconclusive.

When indicated, genetic sequencing for MMR gene variants should begin with MLH1 and MSH2 genes, unless otherwise directed by the results of IHC testing. Standard sequencing methods will not detect large deletions or duplications; when MMR gene variants are expected based on IHC or MSI studies, but none are found by standard sequencing, additional testing for large deletions or duplications is appropriate.

Several Clinical Laboratory Improvement Amendments (CLIA)‒licensed clinical laboratories offer MMR gene variant testing for Lynch syndrome. For example, the GeneTests website (available online at https://www.ncbi.nlm.nih.gov/gtr/all/?term=lynch+syndrome) lists laboratories that offer this service. In at least 1 laboratory, Lynch syndrome variant testing is packaged under a copyrighted name. The COLARIS test (Myriad Genetic Laboratories) includes sequence analysis of MLH1, MSH2, MSH6, and PMS2; large rearrangement analysis for MLH1, MSH2, PMS2, and MSH6 large deletions and duplications; and analysis for large deletions in the EPCAM gene near MSH2. Note that there are 2 versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing). Individualized testing (eg, targeted testing for a family variant) can also be requested. The COLARIS^PLUS test includes full sequence analysis of the MLH1, MSH2, MSH6, PMS2, and MYH genes and rearrangement analysis of MLH1, MSH2, MSH6, MYH, and EPCAM using microarray comparative genomic hybridization analysis, and of PMS2 using multiplex ligationdependent probe amplification analysis.

Similarly, GeneTests lists U.S.-based CLIA-licensed clinical laboratories that provide APC variant testing and those that provide MUTYH variant testing. The COLARIS AP test (Myriad Genetic Laboratories) includes DNA sequencing analysis of the APC and MUTYH genes, as well as analysis of large rearrangements in the APC gene not detected by DNA sequencing.

The Amsterdam II Clinical Criteria (all criteria must be fulfilled) are the most stringent for defining families at high risk for Lynch syndrome (Vasen et al [1999]):

· 3 or more relatives with an associated cancer (CRC, or cancer of the endometrium, small intestine, ureter, or renal pelvis);
· 1 should be a first-degree relative of the other 2;
· 2 or more successive generations affected;
· 1 or more relatives diagnosed before the age of 50 years;
· Familial adenomatous polyposis should be excluded in cases of CRC;
· Tumors should be verified by pathologic examination.
· Modifications:
o EITHER: very small families, which cannot be further expanded, can be considered to have hereditary nonpolyposis colorectal cancer (HNPCC) with only 2 CRCs in first-degree relatives if at least 2 generations have the cancer and at least 1 case of CRC was diagnosed by the age of 55 years;
o OR: in families with 2 first-degree relatives affected by CRC, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.

· CRC diagnosed in a patient who is younger than 50 years old;
· Presence of synchronous or metachronous CRC or other HNPCC‒associated tumors,^a regardless of age;
· CRC with high microsatellite instability histology diagnosed in a patient younger than 60 years old;
· CRC diagnosed in 1 or more first-degree relatives with a Lynch syndrome‒associated tumor, with one of the cancers being diagnosed before 50 years of age;
· CRC diagnosed in 2 or more first or second-degree relatives with HNPCC-related tumors,^a regardless of age.

Multiple risk prediction models that provide quantitative estimates of the likelihood of an MMR variant are available such MMRpro, PREMM5 (Kastrinos et al [2017]), or MMRpredict. National Comprehensive Cancer Network guidelines recommend (category 2A) testing for Lynch syndrome in individuals with a 5% or higher predicted risk of the syndrome on these risk prediction models.

Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical policy updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Previous	Updated	Definition
Mutation	Disease-associated variant	Disease-associated change in the DNA sequence
	Variant	Change in the DNA sequence
	Familial variant	Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

Variant Classification	Definition
Pathogenic	Disease-causing change in the DNA sequence
Likely pathogenic	Likely disease-causing change in the DNA sequence
Variant of uncertain significance	Change in DNA sequence with uncertain effects on disease
Likely benign	Likely benign change in the DNA sequence
Benign	Benign change in the DNA sequence

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Genetic Testing for Familial Adenomatous Polyposis and MUTYH-Associated Polyposis

Clinical Context and Test Purpose

The purpose of genetic testing for FAP and MAP is to

• Identify at-risk relatives of patients with FAP and/or a known adenomatous polyposis coli (APC) genevariant.
• Make a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are at-risk relatives of patients with FAP and/or a known APC variant or those who require a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.

Interventions

The relevant intervention is genetic testing for APC or MUTYH. Commercial testing is available from numerous companies.

Comparators

The following practice is currently being used to make decisions about managing FAP and MAP: no genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be the early detection of colorectal cancer (CRC) and appropriate and timely interventional strategies (eg, endoscopic resection, colectomy) to prolong life.

The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse events from that treatment or undertreatment.

Genetic testing for FAP may be performed at any point during a lifetime. The necessity for genetic testing is guided by the availability of information that alters the risk of an individual of having or developing FAP.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that meet the following eligibility criterion were considered:

• Reported on the analytic sensitivity and specificity and/or diagnostic yield of the test.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The policy for FAP genetic testing was informed by a TEC Assessment (1998).^37,The additional information on attenuated FAP and on MAP diagnostic criteria and genetic testing is based on information from GeneReviews,^38, and from several publications^39,40,41,42, that build on prior, cited research.

The analytic sensitivity and specificity for APC and MUTYH are both 99%. Clinical sensitivity for classic FAP is about 95%; about 90% of pathogenic variants are detected by sequencing^38,43, while 8% to 12% of pathogenic variants are detected by deletion and duplication testing.^44,45, Among Northern European whites, 85% of pathogenic MUTYH variants are detected by the 2 variant test (Y165C, G382D)[4647] and 98% of pathogenic MUTYH variants are detected by full gene sequencing.^46,47,

A comprehensive review of the APC pathogenic variant and its association with classical FAP and attenuated FAP and MAP is beyond the scope of this policy. GeneReviews^38, reported that the likelihood of detecting an APC pathogenic variant is highly dependent on the severity of colonic polyposis^44,48,49,50, and on the family history.^51, Detection rates are higher in classic polyposis (88%) than in nonclassical FAPs such as attenuated colonic phenotypes (57%) or MAP (33%).

Section Summary: Clinically Valid

The analytic and clinical sensitivity and specificity for APC and MUTYH are high. About 90% of pathogenic variants in classical FAP are detected by sequencing while 8% to 12% of pathogenic variants are detected by deletion and duplication testing. Among Northern European whites, 85% of pathogenic MUTYH variants are detected by the 2 variant test, and 98% of pathogenic MUTYH variants are detected by full gene sequencing. The likelihood of detecting an APC pathogenic variant is highly dependent on the severity of colonic polyposis and family history. Detection rates are higher in classic polyposis (88%) than in nonclassical FAPs such as attenuated colonic phenotypes (57%) or MAP (33%).

Clinical Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs were identified assessing the clinical utility of genetic testing for FAP and MAP.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of patients requiring a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome may have clinical utility:

• If the test supports the clinical diagnosis of an attenuated disease, the protocol for endoscopic surveillance is affected and, depending on the situation, may avoid more frequent but unnecessary surveillance or necessitates more frequent surveillance.

• If, in the absence of genetic testing, the diagnosis of colorectal polyposis in at-risk relatives of patients with FAP and/or a known APC variant can only be established by colonoscopy and subsequent histologic examination of removed polyps, which are burdensome.
• If results are negative, the test results may provide release from the intensified screening program resulting in psychological relief.

• Genetic testing for FAP may improve health outcomes by identifying which currently unaffected at-risk family members require intense surveillance or prophylactic colectomy.
• At-risk subjects are considered to be those with greater than ten adenomatous polyps or close relatives of patients with clinically diagnosed FAP or of patients with an identified APC variant.
• The optimal testing strategy is to define the specific genetic variant in an affected family member and then test the unaffected family members to see if they have inherited the same variant.

Testing for the APC variant has no role in the evaluation, diagnosis, or treatment of patients with classical FAP where the diagnosis and treatment are based on the clinical presentation.

Table 1. Summary of Clinical Utility Studies for Genetic Testing for FAP

Study	Study Design and Population	Results
Bjork et al (2000)52,	Observational:195 confirmed cases of FAP underwent ileorectal anastomosis and followed for, on average, 14 y	Cumulative risk of rectal cancer mortality was 7% at 20 y postsurgery and cumulative mortality was 11.1% at the age of 70 y, indicating a substantial risk of developing cancer even after surgery
Järvinen (1992)53,	Observational: 251 individuals from 81 affected families; 76 individuals diagnosed during family screening vs 116 symptomatic individuals with probands	65.5% of symptomatic cases had CRC vs 6.6% cases among those screened during family screening
Vasen et al (1990)54,	Observational: CRC rate compared in 230 confirmed FAP cases; 104 symptomatic and 126 at-risk family members identified by screening	47% of symptomatic cases had CRC at a mean age of 35 y vs 4% at 24 y

CRC: colorectal cancer; FAP: familial adenomatous polyposis.

Section Summary: Clinically Useful

Direct evidence of clinical utility for genetic testing of attenuated FAP is not available. Genetic testing of at-risk relatives of patients with FAP and/or a known APC variant or those requiring a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome may have clinical utility by avoiding burdensome and invasive endoscopic examinations, release from intensified screening program resulting in psychological relief, and may improve health outcomes by identifying currently unaffected at-risk family members who require intense surveillance or prophylactic colectomy.

Lynch Syndrome and CRC Genetic Testing

Clinical Context and Test Purpose

The purpose of genetic testing for Lynch syndrome is to:

• Detect Lynch syndrome in patients diagnosed with CRC or endometrial cancer
• Identify at-risk relatives of patients with a diagnosed Lynch syndrome and/or a known mismatch repair (MMR) variant and/or positive family history meeting Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a risk prediction model,
• Make a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are patients diagnosed with CRC or endometrial cancer or at-risk relatives of patients with a diagnosed Lynch syndrome and/or a known MMR variant and/or positive family history meeting Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a risk prediction model, or those requiring a differential diagnosis of attenuated FAP vs MAP vs Lynch syndrome.

Interventions

The relevant intervention is genetic testing for the MLH1, MSH2, MSH6, PMS2, EPCAM, and/or BRAF V600E genes. Commercial testing is available from numerous companies.

Comparators

The following practice is currently being used to make decisions about managing Lynch syndrome: no genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be early detection of Lynch syndrome and appropriate and timely interventional strategies (eg, increased surveillance, endoscopic resection, colectomy) to prolong life.

The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse effects from that treatment or undertreatment.

Genetic testing for Lynch syndrome may be performed at any point during a lifetime. The necessity for genetic testing is guided by the availability of information that alters the risk of an individual having or developing Lynch syndrome.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that met the following eligibility criterion were considered:

• Reported on the analytic sensitivity and specificity and/or diagnostic yield of the test.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Microsatellite instability (MSI) and immunohistochemical (IHC) screening tests for MMR variants have similar sensitivity and specificity. MSI screening has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6 and a specificity of about 90% for all. IHC screening has sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for each.

The evidence for Lynch syndrome genetic testing in patients with CRC is based on an evidence report conducted for the Agency for Healthcare Research and Quality by Bonis et al (2007),^55, a supplemental assessment to that report contracted by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009),^9, and an EGAPP recommendation (2009) for genetic testing in CRC.^56, Based on the Agency for Healthcare Research and Quality report and supplemental assessment, the EGAPP recommendation concluded the following about genetic testing for MMR variants in patients already diagnosed with CRC:

• Family history, while important information to elicit and consider in each case, has poor sensitivity and specificity as a screening test to determine who should be considered for MMR variant testing and should not be used as a sole determinant or screening test.
• Optional BRAF testing can be used to reduce the number of patients, who are negative for MLH1 expression by IHC, needing MLH1 gene sequencing, thus improving efficiency without reducing sensitivity for MMR variants.

Table 2. Diagnostic Results of the Different Screening Approaches

Screening Approach	Sensitivity (95% CI), %	Specificity (95% CI), %	Diagnostic Yield (95% CI), %
Universal	100 (99.3 to 100)	93 (95 CI, 92.0 to 93.7)	2.2 (95 CI, 1.7 to 2.7)
Bethesda guidelines	87.8 (95 CI, 78.9 to 93.2)	97.5 (95 CI, 96.9 to 98.0)	2.0 (95 CI, 1.5 to 2.4)
Jerusalem recommendations	85.4 (95 CI, 77.1 to 93.6)	96.7 (95 CI, 96.0 to 97.2)	1.9 (95 CI, 1.4 to 2.3)
Selective strategy	95.1 (95 CI, 89.8 to 99.0)	95.5 (95 CI, 94.7 to 96.1)	2.1 (95 CI, 1.6 to 2.6)

CI: confidence interval.

However, the diagnostic yield differences between the screening approaches were small, and the false-positive yield was 2.5% with universal screening. In the selective strategy, 34.8% fewer patients required tumor MMR testing and 28.6% fewer required analyses of MMR variants, resulting in a 4.9% rate of missed Lynch syndrome cases.

Several studies have characterized EPCAM deletions, established their correlation with the presence of EPCAM-MSH2 fusion messenger RNAs (apparently nonfunctional) and with the presence of MSH2 promoter hypermethylation, and, most importantly, have shown the cosegregation of these EPCAM variants with Lynch-like disease in families.^{11,12,13,14,15,16,} Because studies differ slightly in how patients were selected, the prevalence of these EPCAM variants is difficult to estimate but may be in the range of 20% to 40% of patients/families who meet Lynch syndrome criteria, do not have an MMR variant, but have MSI-high tumor tissue. Kempers et al (2011) reported that carriers of an EPCAM deletion had a 75% (95% CI, 65% to 85%) cumulative risk of CRC by age 70 years, which did not differ significantly from that of carriers of an MSH2 deletion (77%; 95% CI, 64% to 90%); mean age at diagnosis was 43 years.^58, However, the cumulative risk of endometrial cancer was low at 12% (95% CI, 0% to 27%) by age 70 compared with carriers of an MSH2 variant (51%; 95% CI, 33% to 69%; p<0.001).

Bouzourene et al (2010) analyzed MLH1 protein abnormalities in 11 patients with sporadic CRC and 16 patients with Lynch syndrome.^10, A BRAF variant was not found in any of the Lynch syndrome patients. MLH1 promoter methylation was only present in one Lynch syndrome patient. However, 8 of the 11 sporadic CRC patients had the BRAF variant, and all 11 patients were MLH1 methylated, suggesting patients with BRAF variants could be excluded from germline testing for Lynch syndrome. Jin et al (2013) evaluated MMR proteins in 412 newly diagnosed CRC patients.^59,MLH1 and PMS2 protein stains were absent in 65 patients who were subsequently tested for BRAF variant. Thirty-six (55%) of the 65 patients had the BRAF V600E variant, thus eliminating the need for further genetic testing or counseling for Lynch syndrome. Capper et al (2013) reported on a technique of V600E IHC testing for BRAF variants on a series of 91 stratified as high MSI CRC patients.^60, The authors detected BRAF-mutated CRC with 100% sensitivity and 98.8% specificity. V600E positive lesions were detected in 21% of MLH1-negative CRC patients who could be excluded from MMR germline testing for Lynch syndrome. Therefore, V600E IHC testing for BRAF could be an alternative to MLH1 promoter methylation analysis. To summarize, BRAF V600E variant or MLH1 promoter methylation testing are optional screening methods that may be used when IHC testing shows a loss of MLH1 protein expression. The presence of BRAF V600E or absence of MLH1 protein expression due to MLH1 promoter methylation rarely occurs in Lynch syndrome and would eliminate the need for further germline variant analysis for a Lynch syndrome diagnosis.^61,

The risk of endometrial cancer in MMR variant carriers has been estimated at 34% (95% CI, 17% to 60%) by age 70, and at 8% for ovarian cancer (95% CI, 2% to 39%) by age 70.^62, Risks do not appear to appreciably increase until after age 40. In a prospective study by Leenen et al (2012), 179 consecutive endometrial cancer patients 70 years of age or younger were analyzed for MSI, using IHC for expression of 4 MMR proteins, MMR gene methylation status, and BRAF variants.^63, Results are presented in Table 3; 92% of patients were older than 50 years of age.

Table 3. Testing Unselected Endometrial Cancer Patients for Lynch Syndrome

Outcomes	N	Percent (95% Confidence Interval)
Microsatellite stable and normal protein staining	137	76
MSI-H and MLH1 absent	32
Sporadic MSI-H	31	17 (13 to 24)
Likely to have Lynch syndrome	11	6 (3 to 11)
Variant-positive	7
No variant found	3
Refused further DNA testing	1

MSI-H: high microsatellite instability.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified assessing the clinical utility of genetic testing for Lynch syndrome.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of patients with colon or endometrial cancer to detect Lynch syndrome has clinical utility:

• To make decisions about the preferred approach for treatment (endoscopic resection, colectomy with ileorectal anastomosis or segmental colectomy).

• If the individuals diagnosed with Lynch syndrome are recommended for screening for Lynch syndrome-associated cancers.
• If, in the absence of genetic testing, the diagnosis of Lynch syndrome in at-risk relatives of patients can only be established by colonoscopy and subsequent histologic examination of excised polyps, which is burdensome.
• If negative test results prompt release from an intensified screening program, thereby reducing an emotional burden.

• If the test supports the clinical diagnosis of Lynch syndrome, the protocol for endoscopic surveillance is affected and, depending on the situation, may avoid more frequent but unnecessary surveillance or necessitates more frequent surveillance.

1. The chain of evidence from well-designed experimental nonrandomized studies is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR variant.
2. Seven studies examined how counseling affected testing and surveillance choices among unaffected family members of Lynch syndrome patients.^{64,65,66,67,68,69,70,} About half of the relatives received counseling, and 95% of them chose MMR gene variant testing. Among those positive for MMR gene variants, uptake of colonoscopic surveillance beginning at age 20 to 25 years was high at 53% to 100%.
• One long-term, nonrandomized controlled study and a cohort study of Lynch syndrome family members found significant reductions in CRC among those who followed recommended colonic surveillance vs those who did not.
• Surveillance and prevention for other Lynch syndrome cancers.
3. The chain of evidence from descriptive studies and expert opinion is inadequate (inconclusive) to demonstrate the clinical utility of testing the probands with Lynch syndrome (ie, the index patient).

1. Subtotal colectomy is recommended as an alternative to segmental resection but has not been shown superior in follow-up studies
2. Although a small body of evidence suggests that MSI-positive tumors are resistant to 5-fluorouracil and more sensitive to irinotecan than MSI-negative tumors, no alteration in therapy according to MSI status has yet been recommended.
3. Surveillance and prevention for other Lynch syndrome cancers:

1. While invasive and not actively recommended, women may choose hysterectomy with salpingo-oophorectomy to prevent gynecologic cancer. In a retrospective study by Schmeler et al (2006), 315 women who chose this option had no gynecologic cancer over 10 years, whereas about one-third of women who did not have surgery developed endometrial cancer, and 5.5% developed ovarian cancer.^71,
2. In a study by Bouzourene et al (2010), surveillance endometrial biopsy detected endometrial cancer and potentially precancerous conditions at earlier stages in those with Lynch syndrome, but results were not statistically significant, and a survival benefit has yet to be shown.^10, Transvaginal ultrasound is not a highly effective surveillance mechanism for endometrial cancer in patients with Lynch syndrome; however, transvaginal ultrasound in conjunction with endometrial biopsy has been recommended for surveillance.
3. Gastroduodenoscopy for gastric cancer surveillance and urine cytology for urinary tract cancer surveillance are recommended based on expert opinion only, in the absence of adequate supporting evidence.

Table 4 summarizes the clinical utility studies assessing genetic testing for Lynch syndrome.

Table 4. Summary of Clinical Validity Studies for Genetic Testing for Lynch Syndrome

Study	Study Design and Population	Results
Yurgelun et al (2012)77,	·Prospective cohort: Examined uptake of risk-reducing strategies in 40 women at risk for LS-associated endometrial cancer. ·Cross-sectional cohort: Examined adoption of risk-reduction strategies using a one-time questionnaire in 77 women at risk of LS-associated endometrial cancer	·In cross-sectional cohort, 58/77 (75%) women reported engaging in endometrial cancer risk-reduction ·Proportion of women engaging in endometrial cancer risk-reduction strategy before genetic testing: 26/40 (65%). At 1-y follow-up, 16/16 (100%) MMR variant carriers were adherent to guidelines for risk-reduction, 9 (56%) of whom had had a prophylactic hysterectomy. By 3 y, 11/16 (69%) MMR variant carriers had a prophylactic hysterectomy. Among women with negative or uninformative genetic test results, none had a prophylactic hysterectomy after testing.
Engel et al (2010)78,	Prospective cohort: Assessed efficacy of annual colonoscopic surveillance in 1126 at-risk individuals from families with LS	99 CRCs found in 90 individuals; 71 were diagnosed by surveillance colonoscopies. Median time between CRCs detected through follow-up colonoscopy and preceding colonoscopy was 11.3 mo.
Järvinen et al (2009)79,	Observational; 609 individuals from 57 LS families; 242 variant-positive and 367 variant-negative followed for cancer incidence over a mean of 11.5 y	No increase in cancer mortality in variant-positive vs -negative individuals; 74 variant-positive individuals had adenomas removed; 48 variant-positive women had prophylactic hysterectomy
Dove-Edwin et al (2005)80,	Prospective observational; 554 individuals from 290 at-risk families with HNPCC or MMR variants followed for 16 y	Estimated 72% decrease in CRC death in screened individuals
De Vos tot Nederveen Cappel et al (2002)81,	Observational; 857 at-risk individuals from 114 HNPCC- or MMR-positive families.	10-y cumulative risk of CRC, 15.7% vs 3.4% for partial vs subtotal colectomy
Syngal et al (1998)82,	Decision analysis model: Assessed impact of decision about immediate prophylactic colectomy, delayed colectomy, or endoscopic surveillance at the time of a positive result on genetic testing	Compared with no intervention, all risk-reduction strategies led gains in life expectancy from 13.5 y for surveillance to 15.6 y for prophylactic proctocolectomy at 25 y of age. Also, surveillance led toQALY gain of 3.1 y vs 0.3 y with subtotal colectomy.
Järvinen et al (1995)83,; Järvinen et al (2000)84,	Observational; 252 at-risk individuals from 20 of 22 families with MMR variants invited for colonoscopy screening every 3 y; 133 agreed; 118 declined. Of those who declined, 8 (15%) had screening examinations outside of the study.	·Screening vs nonscreening ·Incidence of CRC: 4.5% (n=6) vs 11.9% (n=14) (p=0.03) ·6 vs 12 deaths within 10 y (p=0.08)

CRC: colorectal cancer; HNPCC: hereditary nonpolyposis colorectal cancer; LS: Lynch syndrome; MMR: mismatch repair; QALY: quality of life adjusted years.

Kwon et al (2011) developed a Markov Monte Carlo simulation model to compare 6 strategies for Lynch syndrome testing in women with endometrial cancer.^85, Overall, the results suggested that IHC triage of women at any age who had at least one first-degree relative with a Lynch-associated cancer was the most effective strategy for identifying Lynch syndrome and subsequent CRC cases. The model used published prevalence estimates of Lynch syndrome in all endometrial cancer patients of 2% (range, 1%-3%), and of 17% (range, 15%-20%) in endometrial cancer patients with at least 1 first-degree relative with Lynch-associated cancer. Results are presented in Table 5.

Table 5. Modeling of Endometrial Cancer Screening Strategies for Detecting Lynch Syndrome

Testing Strategy	No. Cases Subject to IHC Triage	No. Identified With Lynch Syndrome	No. Subsequent CRC Cases
Amsterdam II criteria	NA	539	2582
Age <50 y, and at least 1 FDR (Lynch-associated cancer)	NA	530	2470
IHC triage	6285	520	2442
IHC triage	16,226	548	2450
IHC triage at any age; at least 1 FDR with Lynch-associated cancer	5786	755	2442
IHC triage all endometrial cancers	45,000	827	2413

CRC: colorectal cancer; FDR: first-degree relative; IHC: immunohistochemical; NA: not available.

Females with Lynch syndrome who choose risk-reducing surgery are encouraged to consider oophorectomy because of the risk of ovarian cancer in Lynch syndrome. In another retrospective cohort study, Obermair et al (2010) found that hysterectomy improved survival among female colon cancer survivors with Lynch syndrome.^86, This study also estimated that, for every 100 women diagnosed with Lynch syndrome-associated CRC, about 23 would be diagnosed with endometrial cancer within 10 years absent a hysterectomy. Data on variant-specific risks have suggested that prophylactic gynecologic surgery benefits for carriers of MSH6 variants may offer less obvious benefits compared with harms, because the lifetime risk of endometrial cancer is lower than for carriers of MLH1 or MSH2 variants, and the lifetime risk of ovarian cancer is similar to the risk for the general population.^62,

However, for carriers of the EPCAM deletion, 3 studies (2011, 2012) reported on 3 cases of endometrial cancer in 103 female carriers who did not undergo a preventative hysterectomy.^58,87,88, Women with EPCAM deletions consequently have a one-fold lower lifetime risk of developing endometrial cancer than with carriers with an MMR variant. This might support a clinical management scenario rather than prophylactic surgery.^87, An alternative to prophylactic surgery is surveillance for endometrial cancer using transvaginal ultrasound and endometrial biopsy. Evidence has suggested that such surveillance significantly reduces the risk of interval cancers, but no evidence as yet has indicated surveillance reduces mortality due to endometrial cancer.^89, Surveillance in Lynch syndrome populations for ovarian cancer has not yet been demonstrated to be successful at improving survival.^89,

Section Summary: Clinically Useful

Direct evidence of clinical utility for genetic testing for Lynch syndrome is not available. Multiple studies have demonstrated clinical utility in testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR variant, in that counseling has been shown to influence testing and surveillance choices among unaffected family members of Lynch syndrome patients. One long-term, nonrandomized controlled study and a cohort study of Lynch syndrome family members found significant reductions in CRC among those who followed and did not follow recommended colonic surveillance. A positive genetic test for an MMR gene variant can also lead to changes in the management of other Lynch syndrome malignancies.

Genetic Testing for Juvenile Polyposis Syndrome and Peutz-Jeghers Syndrome:

Clinical Context and Test Purpose

The purpose of genetic testing for JPS and PJS is:

• To confirm a diagnosis of JPS or PJS in patients suspected of these disorders based on clinical features
• To identify at-risk relatives of patients with a confirmed diagnosis of JPS or PJS.

The following PICOs were used to select literature to inform this review.

Patients

The relevant populations of interest are patients with suspected JPS or PJS and individuals who are at-risk relatives of patients suspected of or diagnosed with a JPS or PJS.

Interventions

The relevant intervention is genetic testing for SMAD4 and BMPR1 (for JPS)and ASATK11 (for PJS). Commercial testing is available from numerous companies.

Comparators

The following practice is currently being used to make decisions about managing JPS and PJS: no genetic testing.

Outcomes

The potential beneficial outcomes of primary interest would be early detection of cancer and appropriate and timely interventional strategies (eg, cancer screening, surgical intervention including polyp resection, gastrectomy, colectomy) to prolong life.

The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse events from that treatment or undertreatment.

Genetic testing for SMAD4 and BMPR1 (for JPS)and ASATK11 (for PJS) may be performed at any point during a lifetime. The necessity for genetic testing is guided by the availability of information that alters the risk of an individual of having or developing JPSandPJS.

Study Selection Criteria

For the evaluation of the clinical validity of the genetic test, studies that met the following eligibility criterion were considered:

• Reported on the diagnostic yield of the test.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Table 6 summarizes the clinical validity studies assessing genetic testing for JPS and PJS.

Table 6. Summary of Clinical Validity Studies Assessing Genetic Testing for JPS and PJS

Study	Study Design and Population	Results
Yang et al (2010)90,	Observational; 17 clinically diagnosed children with PJS	STK 11 variants detected in 29.4% (5/17)
Calva-Cerqueira et al (2009)91,	Observational; 102 unrelated JPS probands analyzed all of whom met clinical criteria for JPS	SMAD4 and BMPR1A variants detected in 41% (42/102) JPS probands
Aretz et al (2007)92,	Observational; 80 unrelated patients (65 met clinical criteria for typical JPS; 15 presumed to have JPS) were examined by direct sequencing for SMAD4, BMPR1A, and PTEN variants	SMAD4 and BMPR1A variants detected in 60% of typical JPS patients and none in presumed JPS patients; overall diagnostic yield, 49%
Volikos et al (2006)93,	Observational; 76 clinically diagnosed with PJS	Detection rate of germline variants was about 80% (59/76)
Aretz et al (2005)94,	Observational; 71 patients (56 met clinical criteria for PJS; 12 presumed to have PJS)	STK11 variant detected in 52% (37/71)

JPS: juvenile polyposis syndrome; PJS: Peutz-Jeghers syndrome.

Section Summary: Clinically Valid

The likelihood of detecting a pathogenic variant is highly dependent on the presence of clinical features and family history. Detection rates for JPS and PJS have been reported to be between 60% and 41% and 29.4% and 80%, respectively.

Clinical Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

No RCTs were identified assessing the clinical utility of genetic testing for JPS and PJS.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Genetic testing of patients with suspected JPS and PJS has clinical utility:

• To make decisions about a preferred approach for treatment (endoscopic resection, colectomy with ileorectal anastomosis, segmental colectomy).

• If the individuals diagnosed with JPS and PJS are recommended for screening for JPS and PJS-associated cancers.
• If, in the absence of genetic testing, the diagnosis of JPS and PJS in at-risk relatives of patients can only be established by colonoscopy and subsequent histologic examination of excised polyps, which is burdensome.
• If negative test results prompt release from an intensified screening program, thereby reducing an emotional burden.

Table 7. Summary of Clinical Utility Studies for Genetic Testing for JPS and PJS

Study	Study Design and Population	Results
Aytac et al (2015)95,	Observational: 35 patients had germline variants in BMPR1A (8 patients) or SMAD4 (27) with a median follow-up of 11 y	No patient was diagnosed with cancer in the BMPR1A group, whereas 4 men with a SMAD4 variant developed GI (n=3) or extraintestinal (n=1) cancer. The GI cancer risk in patients with JPS and a SMAD4 variant was 11% (3/27).
Resta et al (2013)96,	Observational: 119 patients with PJS	Cancer occurred in 31/119 patients (RR for overall cancer risk, 15.1); mean age at first cancer diagnosis was 41 y. Kaplan-Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60, and 65 y, respectively.
Lier et al (2010)36,	Systematic review: 21 original articles, 20 cohort studies, and 1 meta-analysis (total N=1644 PJS patients)	349 patients developed 384 malignancies at average age of 42 y. Lifetime risk for any cancer varied between 37% and 93% with RRs ranging from 9.9 to 18 vs the general population.
Salloch et al (2009)97,	Observational: 31 patients with PJS; STK11 variants in 16/22 families	10 carcinomas detected in 6 patients resulting in a cancer risk of 65% up to the age of 65 y; surveillance strategy detected 50% of cancers (n=5) at an early potentially curable stage
Brosens et al (2007)29,	Observational: 84 patients with JPS contributing 1652.2 person-years of follow-up vs general population of the U.S. (SEER data)	RR of CRC was 34.0 (95% CI, 14.4 to 65.7); cumulative lifetime risk for CRC was 38.7%; mean age of diagnosis of CRC, 43.9 y

CI: confidence interval; CRC: colorectal cancer; GI: gastrointestinal; JPS: juvenile polyposis syndrome; PJS: Peutz-Jeghers syndrome; RR: relative risk.

Section Summary: Clinically Useful

Direct evidence of the clinical utility for genetic testing of JPS or PJS is not available. Genetic testing of patients with suspected JPS or PJS or individuals who are at-risk relatives of patients suspected of or diagnosed with a polyposis syndrome or PJS may have clinical utility by avoiding burdensome and invasive endoscopic examinations, release from intensified screening program resulting in psychological relief, and may improve health outcomes by identifying currently unaffected at-risk family members who require intense surveillance or prophylactic colectomy.

Summary of Evidence

For individuals who are suspected of attenuated FAP, MAP, and Lynch syndrome who receive genetic testing for APC, or are at-risk relatives of patients with FAP who receive genetic testing for MUTYH after a negative APC test result, the evidence includes a TEC Assessment. The relevant outcomes are overall survival (OS), disease-specific survival, and test accuracy and validity. For patients with an APC variant, enhanced surveillance and/or prophylactic treatment will reduce the future incidence of colon cancer and improve health outcomes. A related familial polyposis syndrome, MAP syndrome, is associated with variants in the MUTYH gene. Testing for this genetic variant is necessary when the differential diagnosis includes both FAP and MAP because distinguishing between the two leads to different management strategies. Depending on the presentation, Lynch syndrome may be part of the same differential diagnosis. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who (1) are suspected of attenuated FAP, MAP, and Lynch syndrome, or (2) have colon cancer, or (3) have endometrial cancer and a first-degree relative diagnosed with a Lynch-associated cancer, or (4) are at-risk relatives of patients with Lynch syndrome, or (5) are without colon cancer but with a family history meeting Amsterdam or Revised Bethesda criteria, or documentation of 5% or higher predicted risk of the syndrome on a validated risk prediction model, who receive genetic testing for MMR genes, the evidence includes an Agency for Healthcare Research and Quality report, a supplemental assessment to that report by the Evaluation of Genomic Applications in Practice and Prevention Working Group, and an Evaluation of Genomic Applications in Practice and Prevention recommendation for genetic testing in CRC. The relevant outcomes are OS, disease-specific survival, and test accuracy and validity. A chain of evidence from well-designed experimental nonrandomized studies is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known variant in an MMR gene, in that counseling has been shown to influence testing and surveillance choices among unaffected family members of Lynch syndrome patients. One long-term, nonrandomized controlled study and a cohort study of Lynch syndrome family members found significant reductions in CRC among those who followed recommended colonic surveillance. A positive genetic test for an MMR variant can also lead to changes in the management of other Lynch syndrome malignancies. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who warrant Lynch testing, screen negative on MMR testing, but positive for microsatellite instability and lack MSH2 protein expression who receive genetic testing for EPCAM variants, the evidence includes variant prevalence studies and case series. The relevant outcomes are OS, disease-specific survival, and test accuracy and validity. Studies have shown an association between EPCAM variants and Lynch-like disease in families, and the cumulative risk for CRC is similar to carriers of an MSH2 variant. Identification of an EPCAM variant could lead to changes in management that improve health outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CRC in whom MLH1 protein is not expressed on immunohistochemical analysis who receive genetic testing for BRAF V600E or MLH1 promoter methylation, the evidence includes case series. The relevant outcomes are OS, disease-specific survival, and test accuracy and validity. Studies have shown, with high sensitivity and specificity, an association between BRAF V600E variant and MLH1 promoter methylation with sporadic CRC. Therefore, this type of testing could eliminate the need for further genetic testing or counseling for Lynch syndrome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who (1) are suspected of JPS or PJS or (2) are at-risk relatives of patients suspected of or diagnosed with JPS or PJS who receive genetic testing for SMAD4,BMPR1A, or STK11 genes, respectively, the evidence includes multiple observational studies. The relevant outcomes are OS, disease-specific survival, and test accuracy and validity. Studies have shown, with high sensitivity and specificity, an association between SMAD4 and BMPR1A and STK11variants with JPSand PJS, respectively. Direct evidence of clinical utility for genetic testing of a JPS or PJS is not available. Genetic testing may have clinical utility by avoiding burdensome and invasive endoscopic examinations, release from intensified screening program resulting in psychological relief, and may improve health outcomes by identifying currently unaffected at-risk family members who require intense surveillance or prophylactic colectomy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 3 physician specialty societies and 3 academic medical centers while this policy was under review in 2009. In general, those providing input agreed with the overall approach described in this policy.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The NCCN guidelines (v.2.2019) are summarized in Table 8.^31,

Table 8. Criteria for Evaluation of Lynch Syndrome

Criteria for the Evaluation of Lynch Syndrome

Known LS variant in the family

An individual with colorectal or endometrial cancer and any of the following: Diagnosed <50 y Another synchronous or metachronous LS-related cancera ≥1 first-degree or second-degree relative with LS-relateda cancer diagnosed <50 y ≥2 first-degree or second-degree relatives with LS-relateda cancers regardless of age

An individual with colorectal or endometrial cancer at any age with tumor showing evidence of MMR deficiency, either by MSI or loss of MMR protein expressionb

Family history of any of the following: ≥1 first-degree relative with colorectal or endometrial cancer diagnosed <50 y ≥1 first-degree relative with colorectal or endometrial cancer and another synchronous or metachronous LS-related cancera ≥2 first-degree or second-degree relatives with LS-related cancer,a including ≥1 diagnosed <50 y ≥3 first-degree or second-degree relatives with LS-related cancers,a regardless of age

An individual with an LS-related cancera or unaffected individual with ≥5% riskc of having an MMR gene variant based on predictive models (PREMM5, MMRpro, MMRpredict)

An individual with a colorectal tumor with MSI-high histology (ie, presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern) diagnosed ≤60 y

LS: Lynch syndrome; MMR: mismatch repair; MSI: microsatellite instability.

^a LS-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, brain (usually glioblastoma), biliary tract, small intestinal cancers, as well as sebaceous carcinomas, and keratoacanthomas as seen in Muir-Torre syndrome.

^b Tumor screening for MMR deficiency is appropriate for all colorectal and endometrial cancers regardless of age at diagnosis, however, germline genetic testing is generally reserved for patients with early age at diagnosis; positive family history; or abnormal tumor testing results; MSI or loss of MMR protein expression.

^c There are recent data that resulted in a lower threshold of ≥2.5% for the PREMM5 predictive model risk for having an MMR gene variant. Based on these data, it is reasonable for testing to be done based on the ≥2.5% score result and clinical judgment. Of note, with the lower threshold, there is an increase in sensitivity, but a decrease in specificity. It is not known how this applies to the general population of unaffected individuals.

Additionally, theNCCN guidelines (v.2.2019) recommend screening for Lynch syndrome in all endometrial cancer patients younger than 50 years.^98, Genetic testing is recommended for at-risk family members of patients with positive variants in MLH1, MSH2, MSH6, and PMS2. The NCCN guidelines also indicate BRAF V600E testing or MLH1 promoter methylation testing may be used when MLH1 is not expressed in the tumor on immunohistochemical analysis to exclude a diagnosis of Lynch syndrome. These guidelines also address familial adenomatous polyposis (classical and attenuated) and MUTYH-associated polyposis and are consistent with the information provided in this policy.

The NCCN guidelines for colon cancer (v.2.2019)^99, and for CRC screening (v.3.2019)^100, recommend CRC patients treated with curative-intent surgery undergo surveillance colonoscopy at 1 year postsurgery and, if normal, again in 3 years, then every 5 years based on findings. However, because of the high likelihood of cancer, colonoscopy is recommended every one to two years throughout life for patients with Lynch syndrome before cancer diagnosis; and the high likelihood of a second primary cancer is based on a first cancer diagnosis.^81,The NCCN guidelines on genetic/familial high-risk assessment for colorectal indicate for MLH1, MSH2, and EPCAM variant carriers that surveillance with colonoscopy should begin "at age 20 to 25 years or 2 to 5 years before the earliest colon cancer if it is diagnosed before age 25 years and repeat every 1 to 2 years."^31, "MSH6 variant carriers should begin surveillance with colonoscopy at age 30 to 35 years, and PMS2 carriers should begin surveillance at age 35 to 40 years. However, screening may need to be initiated earlier in some families, depending on the ages of cancers observed in family members. This screening is recommended every 2 to 3 years until age 40 or 50 years for MSH6 and PMS2 variant carriers, respectively, at which time colonoscopy should be performed every 1 to 2 years." "If the patient is not a candidate for routine surveillance, subtotal colectomy may be considered."

The NCCN guidelines for colon cancer recommend that patients 70 years or younger plus those older than 70 years of age who meet the Bethesda guidelines be tested for the mismatch repair (MMR) protein for possible Lynch syndrome.^99, These guidelines also indicate all colon cancer patients should be questioned about family history and considered for risk assessment as per the NCCN colorectal screening guidelines. The NCCN guidelines for uterine neoplasm also recommend universal screening for MMR genes.^98,

There are limited data on the efficacy of various screening modalities in juvenile polyposis syndrome and Peutz-Jeghers syndrome. The NCCN cancer risk and surveillance 2 category 2A recommendations for these indications are summarized in Tables 9 and 10.^31,

Table 9. Risk and Surveillance Guidelines for Peutz-Jeghers Syndrome

Site	Lifetime Risk, %	Screening Procedure and Interval	Initiation Age, y
Breast	45-50	Mammogram and breast MRI annually Clinical breast exam every 6 mo	»25 y
Colon	39	Colonoscopy every 2-3 y	Late teens
Stomach	29	Upper endoscopy every 2-3 y	Late teens
Small intestine	13	Small bowel visualization (CT or MRI enterography or video capsule endoscopy baseline at 8-10 y with follow-up interval based on findings but at least by age 18, then every 2-3 y, though this may be individualized, or with symptoms)	»8 to 10 y
Pancreas	11-36	Magnetic resonance cholangiopancreatography with contrast or endoscopic ultrasound every 1-2 h	»30 to 35 y
Ovary(typically benign sex cord/Sertoli cell tumors) Cervix (typically cervical adenoma malignum) Uterus	18-21 10 9	Pelvic examination and Pap smear annually Consider transvaginal ultrasound	»18 to 20 y
Testes (typically sex cord/Sertoli cell tumors)		Annual testicular exam and observation for feminizing changes	»10 y
Lung	15-17	Provide education about symptoms and smoking cessation No other specific recommendations have been made

CT: computed tomography; MRI: magnetic resonance imaging.

Table 10. Risk and Surveillance Guidelines for Juvenile Polyposis Syndrome

Site	Lifetime Risk, %	Screening Procedure and Interval	Initiation Age, y
Colon	40-50	Colonoscopy every year if polyps are found and every 2-3 y if no polyps are founda	»15 y
Stomach	21 if multiple polyps	Upper endoscopy annually if polyps are found and every 2-3 y if no polyps are founda	»15 y
Small intestine	Rare, undefined	No recommendations made
Pancreas	Rare, undefined	No recommendations made
HHT	Undefined	In individuals with SMAD4 variants, screen for vascular lesions associated with HHT	Within first 6 mo of age

HHT: hereditary hemorrhagic telangiectasia.

^a In families without an identified genetic variants, consider substituting endoscopy every 5 y beginning at age 20 and every 10 y beginning at age 40 y in patients in whom no polyps are found.

American College of Gastroenterology

The American College of Gastroenterology (2015) issued practice guidelines for the management of patients with hereditary gastrointestinal cancer syndromes.^26,

For Lynch syndrome, the College recommended:

“All newly diagnosed colorectal cancers (CRCs) should be evaluated for mismatch repair deficiency.

Analysis may be done by immunohistochemical testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for microsatellite instability. Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis for MLH1 promoter hypermethylation.

Individuals who have a personal history of a tumor showing evidence of mismatch repair deficiency (and no demonstrated BRAF variant or hypermethylation of MLH1), a known family variant associated with LS [Lynch syndrome], or a risk of ≥5% chance of LS based on risk prediction models should undergo genetic evaluation for LS.^101,

Genetic testing of patients with suspected LS should include germline variant genetic testing for the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes or the altered gene(s) indicated by IHC testing.”

For adenomatous polyposis syndromes, the College recommended:

“Familial adenomatous polyposis (FAP)/MUTYH-associated polyposis/attenuated polyposis

Individuals who have a personal history of >10 cumulative colorectal adenomas, a family history of one of the adenomatous polyposis syndromes, or a history of adenomas and FAP-type extracolonic manifestations (duodenal/ampullary adenomas, desmoid tumors, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium, epidermal cysts, osteomas) should undergo assessment for the adenomatous polyposis syndromes.

Genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene variant analysis.”

For juvenile polyposis syndrome, the College recommended:

“Genetic evaluation of a patient with possible JPS [juvenile polyposis syndrome] should include testing for SMAD4 and BMPR1A mutations”

“Surveillance of the gastrointestinal (GI) tract in affected or at-risk JPS patients should include screening for colon, stomach, and small bowel cancers (strong recommendation, very low quality of evidence).

Colectomy and ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis is indicated for polyp-related symptoms, or when the polyps cannot be managed endoscopically (strong recommendation, low quality of evidence).

Cardiovascular examination for and evaluation for hereditary hemorrhagic telangiectasia should be considered for SMAD4 mutation carriers (conditional recommendation, very low quality of evidence).”

For Peutz-Jeghers syndrome, the College recommended:

“Genetic evaluation of a patient with possible PJS [Peutz-Jeghers syndrome] should include testing for STK11 mutations.”

“Surveillance in affected or at-risk PJS patients should include monitoring for colon, stomach, small bowel, pancreas, breast, ovary, uterus, cervix, and testes cancers. Risk for lung cancer is increased, but no specific screening has been recommended. It would seem wise to consider annual chest radiograph or chest computed tomography (CT) in smokers (conditional recommendation, low quality of evidence).”

American Society of Clinical Oncology and Society of Surgical Oncology

The American Society of Clinical Oncology (2015) concluded the European Society for Medical Oncology clinical guidelines published in 2013 were based on the most relevant scientific evidence and therefore endorsed them with minor qualifying statements (in bold italics).^102, The recommendations as related to genetic testing hereditary CRC syndromes are summarized below:

• “Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all CRC patients. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines.
• If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.
• If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).
• Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis…
• Patients with multiple colorectal adenomas should be considered for full germline genetic testing of APC and/or MUTYH.
• Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered.”

No U.S. Preventive Services Task Force recommendations for genetic testing of Lynch syndrome and other inherited colon cancer syndromes have been identified.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Unpublished
NCT01646112	Living in Lynch Syndrome Limbo: Exploring the Meaning of Uncertain Genetic Test Results	34	Feb 2016 (completed)
NCT01850654	Ohio Colorectal Cancer Prevention Initiative: Universal Screening for Lynch Syndrome	4000	Sep 2017 (completed)

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
Genetic Testing for Inherited Susceptibility to Colon Cancer Including Microsatellite Instability
Adenomatous Polyposis Coli (APC)
APC (Adenomatous Polyposis Coli)
Colon Cancer, Genetic Testing for Inherited Susceptibility to
Familial Adenomatous Polyposis (FAP)
FAP (Familial Adenomatous Polyposis)
Inherited Intestinal Polyposis Syndromes, Genetic Testing for
Lynch Syndrome, Genetic Testing for
Microsatellite Instability (MSI)
Colaris
Colaris AP
HNPCC (Hereditary Nonpolyposis Colorectal Cancer), Genetic Testing
Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Genetic Testing
EPCAM Mutations, Genetic Testing
MMR Gene Mutations, Genetic Testing
MUTYH Gene Mutations, Genetic Testing
BRAF V600E, Genetic Testing
MLH1 Promoter Methylation, Genetic Testing
MLH1
MSH2
MSH6
PMS2
MLH3
MSI (Microsatellite Instability)
SMAD4 Gene Variants, Genetic Testing for
BMPR1A Gene Variants, Genetic Testing for
STK11 Gene Variants, Genetic Testing for
Juvenile Polyposis Syndrome, Genetic Testing for
Peutz-Jeghers Syndrome, Genetic Testing for

References:
1. Vogt S, Jones N, Christian D, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. Dec 2009;137(6):1976-1985 e1971-1910. PMID 19732775.

2. Balmana J, Castells A, Cervantes A. Familial colorectal cancer risk: ESMO Clinical Practice Guidelines. Ann Oncol. May 2010;21(Suppl 5):v78-81. PMID 20555108.

3. Gala M, Chung DC. Hereditary colon cancer syndromes. Semin Oncol. Aug 2011;38(4):490-499. PMID 21810508.

4. Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet. Jun 2005;42(6):491-496. PMID 15937084.

5. Guindalini RS, Win AK, Gulden C, et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology. Nov 2015;149(6):1446-1453. PMID 26248088.

6. Sinn DH, Chang DK, Kim YH, et al. Effectiveness of each Bethesda marker in defining microsatellite instability when screening for Lynch syndrome. Hepatogastroenterology. May-Jun 2009;56(91-92):672-676. PMID 19621678.

7. Wu Y, Berends MJ, Mensink RG, et al. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. Nov 1999;65(5):1291- 1298. PMID 10521294.

8. Goel A, Nagasaka T, Spiegel J, et al. Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer. Clin Gastroenterol Hepatol. Nov 2010;8(11):966-971. PMID 20655395.

9. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. Jan 2009;11(1):42-65. PMID 19125127.

10. Bouzourene H, Hutter P, Losi L, et al. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. Jun 2010;9(2):167-172. PMID 19949877.

11. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. Aug 2009;48(8):737-744. PMID 19455606.

12. Kloor M, Voigt AY, Schackert HK, et al. Analysis of EPCAM protein expression in diagnostics of Lynch syndrome. J Clin Oncol. Jan 10 2011;29(2):223-227. PMID 21115857.

13. Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. Apr 2011;32(4):407-414. PMID 21309036.

14. Kovacs ME, Papp J, Szentirmay Z, et al. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. Feb 2009;30(2):197-203. PMID 19177550.

15. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. Jan 2009;41(1):112-117. PMID 19098912.

16. Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated lynch syndrome cases. J Mol Diagn. Jan 2011;13(1):93-99. PMID 21227399.

17. Hesson LB, Hitchins MP, Ward RL. Epimutations and cancer predisposition: importance and mechanisms. Curr Opin Genet Dev. Jun 2010;20(3):290-298. PMID 20359882.

18. Hitchins MP. Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet. Oct 2010;70:201-243. PMID 20920750.

19. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. Jun 1999;116(6):1453-1456. PMID 10348829.

20. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. Feb 18 2004;96(4):261-268. PMID 14970275.

21. Kastrinos F, Uno H, Ukaegbu C, et al. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol. Jul 01 2017;35(19):2165-2172. PMID 28489507.

22. Latchford AR, Neale K, Phillips RK, et al. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. Oct 2012;55(10):1038-1043. PMID 22965402.

23. Howe JR, Roth S, Ringold JC, et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. May 15 1998;280(5366):1086-1088. PMID 9582123.

24. Fogt F, Brown CA, Badizadegan K, et al. Low prevalence of loss of heterozygosity and SMAD4 mutations in sporadic and familial juvenile polyposis syndrome-associated juvenile polyps. Am J Gastroenterol. Oct 2004;99(10):2025-2031. PMID 15447767.

25. Burger B, Uhlhaas S, Mangold E, et al. Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. Am J Med Genet. Jul 1 2002;110(3):289-291. PMID 12116240.

26. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Feb 2015;110(2):223-262; quiz 263. PMID 25645574.

27. Grotsky HW, Rickert RR, Smith WD, et al. Familial juvenile polyposis coli. A clinical and pathologic study of a large kindred. Gastroenterology. Mar 1982;82(3):494-501. PMID 7054044.

28. Schreibman IR, Baker M, Amos C, et al. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol. Feb 2005;100(2):476-490. PMID 15667510.

29. Brosens LA, van Hattem A, Hylind LM, et al. Risk of colorectal cancer in juvenile polyposis. Gut. Jul 2007;56(7):965-967. PMID 17303595.

30. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. Mar 13 2004;363(9412):852-859. PMID 15031030.

31. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed August 22, 2019.

32. Olschwang S, Markie D, Seal S, et al. Peutz-Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J Med Genet. Jan 1998;35(1):42-44. PMID 9475093.

33. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet. Jan 1998;18(1):38-43. PMID 9425897.

34. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. Jan 8 1998;391(6663):184-187. PMID 9428765.

35. Hernan I, Roig I, Martin B, et al. De novo germline mutation in the serine-threonine kinase STK11/LKB1 gene associated with Peutz-Jeghers syndrome. Clin Genet. Jul 2004;66(1):58-62. PMID 15200509.

36. van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. Jun 2010;105(6):1258-1264; author reply 1265. PMID 20051941.

37. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Genetic Testing for Inherited Susceptibility to Colorectal Cancer: Part I Adenomatous Polyposis Coli Gene Mutations. TEC Assessments. 1998;Volume 13:Tab 10. PMID.

38. Jasperson KW, Patel SG, Ahnen DJ. APC-Associated Polyposis Conditions. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews. Seattle, WA: University of Washington; 2017.

39. Kastrinos F, Syngal S. Recently identified colon cancer predispositions: MYH and MSH6 mutations. Semin Oncol. Oct 2007;34(5):418-424. PMID 17920897.

40. Lefevre JH, Parc Y, Svrcek M, et al. APC, MYH, and the correlation genotype-phenotype in colorectal polyposis. Ann Surg Oncol. Apr 2009;16(4):871-877. PMID 19169759.

41. Avezzu A, Agostini M, Pucciarelli S, et al. The role of MYH gene in genetic predisposition to colorectal cancer: another piece of the puzzle. Cancer Lett. Sep 18 2008;268(2):308-313. PMID 18495334.

42. Balaguer F, Castellvi-Bel S, Castells A, et al. Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol. Mar 2007;5(3):379-387. PMID 17368238.

43. Lagarde A, Rouleau E, Ferrari A, et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. Oct 2010;47(10):721-722. PMID 20685668.

44. Aretz S, Stienen D, Uhlhaas S, et al. Large submicroscopic genomic APC deletions are a common cause of typical familial adenomatous polyposis. J Med Genet. Feb 2005;42(2):185-192. PMID 15689459.

45. Bunyan DJ, Eccles DM, Sillibourne J, et al. Dosage analysis of cancer predisposition genes by multiplex ligation- dependent probe amplification. Br J Cancer. Sep 13 2004;91(6):1155-1159. PMID 15475941.

46. Out AA, Tops CM, Nielsen M, et al. Leiden Open Variation Database of the MUTYH gene. Hum Mutat. Nov 2010;31(11):1205-1215. PMID 20725929.

47. Nielsen M, Lynch H, Infante E, et al. MUTYH-Associated Polyposis. In: Pagon RA, Adam MP, Ardinger HH, eds. GeneReviews Seattle, WA: University of Washington; 2012.

48. Sieber OM, Lamlum H, Crabtree MD, et al. Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or multiple colorectal adenomas. Proc Natl Acad Sci U S A. Mar 05 2002;99(5):2954-2958. PMID 11867715.

49. Aretz S, Uhlhaas S, Goergens H, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. Aug 15 2006;119(4):807-814. PMID 16557584.

50. Michils G, Tejpar S, Thoelen R, et al. Large deletions of the APC gene in 15% of mutation-negative patients with classical polyposis (FAP): a Belgian study. Hum Mutat. Feb 2005;25(2):125-134. PMID 15643602.

51. Truta B, Allen BA, Conrad PG, et al. A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history. Fam Cancer. Jun 2005;4(2):127-133. PMID 15951963.

52. Bjork JA, Akerbrant HI, Iselius LE, et al. Risk factors for rectal cancer morbidity and mortality in patients with familial adenomatous polyposis after colectomy and ileorectal anastomosis. Dis Colon Rectum. Dec 2000;43(12):1719-1725. PMID 11156457.

53. Jarvinen HJ. Epidemiology of familial adenomatous polyposis in Finland: impact of family screening on the colorectal cancer rate and survival. Gut. Mar 1992;33(3):357-360. PMID 1314763.

54. Vasen HF, Griffioen G, Offerhaus GJ, et al. The value of screening and central registration of families with familial adenomatous polyposis. A study of 82 families in The Netherlands. Dis Colon Rectum. Mar 1990;33(3):227-230. PMID 2155763.

55. Bonis PA, Trikalinos TA, Chung M, et al. Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications (Evidence Report/Technology Assessment No. 150). Rockville, MD: Agency for Healthcare Research and Quality; 2007.

56. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. Jan 2009;11(1):35-41. PMID 19125126.

57. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. Oct 17 2012;308(15):1555-1565. PMID 23073952.

58. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion- positive Lynch syndrome: a cohort study. Lancet Oncol. Jan 2011;12(1):49-55. PMID 21145788.

59. Jin M, Hampel H, Zhou X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Clin Pathol. Aug 2013;140(2):177-183. PMID 23897252.

60. Capper D, Voigt A, Bozukova G, et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer. Oct 1 2013;133(7):1624-1630. PMID 23553055.

61. Kastrinos F, Syngal S. Screening patients with colorectal cancer for Lynch syndrome: what are we waiting for? J Clin Oncol. Apr 1 2012;30(10):1024-1027. PMID 22355054.

62. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. Jun 8 2011;305(22):2304-2310. PMID 21642682.

63. Leenen CH, van Lier MG, van Doorn HC, et al. Prospective evaluation of molecular screening for Lynch syndrome in patients with endometrial cancer

64. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. May 05 2005;352(18):1851-1860. PMID 15872200.

65. Aktan-Collan K, Mecklin JP, Jarvinen H, et al. Predictive genetic testing for hereditary non-polyposis colorectal cancer: uptake and long-term satisfaction. Int J Cancer. Jan 20 2000;89(1):44-50. PMID 10719730.

66. Aktan-Collan K, Haukkala A, Pylvanainen K, et al. Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing. J Med Genet. Nov 2007;44(11):732-738. PMID 17630403.

67. Stanley AJ, Gaff CL, Aittomaki AK, et al. Value of predictive genetic testing in management of hereditary non- polyposis colorectal cancer (HNPCC). Med J Aust. Apr 03 2000;172(7):313-316. PMID 10844916.

68. Hadley DW, Jenkins J, Dimond E, et al. Genetic counseling and testing in families with hereditary nonpolyposis colorectal cancer. Arch Intern Med. Mar 10 2003;163(5):573-582. PMID 12622604.

69. Lerman C, Hughes C, Trock BJ, et al. Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA. May 05 1999;281(17):1618-1622. PMID 10235155.

70. Codori AM, Petersen GM, Miglioretti DL, et al. Attitudes toward colon cancer gene testing: factors predicting test uptake. Cancer Epidemiol Biomarkers Prev. Apr 1999;8(4 Pt 2):345-351. PMID 10207639.

71. Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med. Jan 19 2006;354(3):261-269. PMID 16421367.

72. Fitzgibbons RJ, Jr., Lynch HT, Stanislav GV, et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg. Sep 1987;206(3):289-295. PMID 3632093.

73. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA. Mar 19 1997;277(11):915-919. PMID 9062331.

74. Van Dalen R, Church J, McGannon E, et al. Patterns of surgery in patients belonging to amsterdam-positive families. Dis Colon Rectum. May 2003;46(5):617-620. PMID 12792437.

75. de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P, et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut. Dec 2003;52(12):1752-1755. PMID 14633956.

76. Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol. Oct 1 2006;24(28):4642-4660. PMID 17008706.

77. Yurgelun MB, Mercado R, Rosenblatt M, et al. Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome. Gynecol Oncol. Dec 2012;127(3):544-551. PMID 22940489.

78. Engel C, Rahner N, Schulmann K, et al. Efficacy of annual colonoscopic surveillance in individuals with hereditary nonpolyposis colorectal cancer. Clin Gastroenterol Hepatol. Feb 2010;8(2):174-182. PMID 19835992.

79. Jrvinen HJ, Renkonen-Sinisalo L, Aktan-Collan K, et al. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation-negative family members. J Clin Oncol. Oct 01 2009;27(28):4793-4797. PMID 19720893.

80. Dove-Edwin I, Sasieni P, Adams J, et al. Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family history of colorectal cancer: 16 year, prospective, follow-up study. BMJ. Nov 05 2005;331(7524):1047. PMID 16243849.

81. de Vos tot Nederveen Cappel WH, Nagengast FM, Griffioen G, et al. Surveillance for hereditary nonpolyposis colorectal cancer: a long-term study on 114 families. Dis Colon Rectum. Dec 2002;45(12):1588-1594. PMID 12473880.

82. Syngal S, Weeks JC, Schrag D, et al. Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations. Ann Intern Med. Nov 15 1998;129(10):787- 796. PMID 9841584.

83. Jrvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. May 1995;108(5):1405-1411. PMID 7729632.

84. Jrvinen HJ, Aarnio M, Mustonen H, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. May 2000;118(5):829-834. PMID 10784581.

85. Kwon JS, Scott JL, Gilks CB, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. Jun 1 2011;29(16):2247-2252. PMID 21537049.

86. Obermair A, Youlden DR, Young JP, et al. Risk of endometrial cancer for women diagnosed with HNPCC- related colorectal carcinoma. Int J Cancer. Dec 1 2010;127(11):2678-2684. PMID 20533284.

87. Grandval P, Baert-Desurmont S, Bonnet F, et al. Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion. Clin Genet. Jul 2012;82(1):97-99. PMID 22243433.

88. Lynch HT, Riegert-Johnson DL, Snyder C, et al. Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion. Am J Gastroenterol. Oct 2011;106(10):1829-1836. PMID 21769135.

89. Auranen A, Joutsiniemi T. A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand. May 2011;90(5):437-444. PMID 21306348.

90. Yang HR, Ko JS, Seo JK. Germline mutation analysis of STK11 gene using direct sequencing and multiplex ligation-dependent probe amplification assay in Korean children with Peutz-Jeghers syndrome. Dig Dis Sci. Dec 2010;55(12):3458-3465. PMID 20393878.

91. Calva-Cerqueira D, Chinnathambi S, Pechman B, et al. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. Jan 2009;75(1):79-85. PMID 18823382.

92. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. Nov 2007;44(11):702-709. PMID 17873119.

93. Volikos E, Robinson J, Aittomaki K, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz- Jeghers syndrome. J Med Genet. May 2006;43(5):e18. PMID 16648371.

94. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat. Dec 2005;26(6):513-519. PMID 16287113.

95. Aytac E, Sulu B, Heald B, et al. Genotype-defined cancer risk in juvenile polyposis syndrome. Br J Surg. Jan 2015;102(1):114-118. PMID 25389115.

96. Resta N, Pierannunzio D, Lenato GM, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study. Dig Liver Dis. Jul 2013;45(7):606-611. PMID 23415580.

97. Salloch H, Reinacher-Schick A, Schulmann K, et al. Truncating mutations in Peutz-Jeghers syndrome are associated with more polyps, surgical interventions and cancers. Int J Colorectal Dis. Jan 2010;25(1):97-107. PMID 19727776.

98. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf Accessed August 22, 2019.

99. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2019. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed August 22, 2019.

100. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 2.2019. http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed August 22, 2019.

101. Kastrinos F, Steyerberg EW, Mercado R, et al. The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history. Gastroenterology. Jan 2011;140(1):73-81. PMID 20727894.

102. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. Jan 10 2015;33(2):209-217. PMID 25452455.

Codes
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81201 - 81203
81210
81288
81292 - 81294
81295 - 81297
81298 - 81300
81301
81317 - 81319
81403
81435
81436
0101U
0130U