Genetic Testing for Cancer Susceptibility

Genetic testing for cancer susceptibility may be approached by a focused method that involves testing for well-characterized variants based on clinical suspicion of which gene(s) may be the cause of the heritable or familial cancer. Panel testing involves evaluating multiple variants in multiple genes at one time.

Multiple commercial companies and medical center laboratories offer genetic testing panels that use next-generation sequencing (NGS) methods for hereditary cancers. NGS is one of several methods that use massively parallel platforms to allow the sequencing of large stretches of DNA. Panel testing is potentially associated with greater efficiencies in the evaluation of genetic diseases; however, it may provide information on genetic variants of uncertain clinical significance or findings that would not lead to changes in patient management. Currently available panels do not include all genes associated with hereditary cancer syndromes. Also, these panels may not test for variants (ie, single nucleotide variants), which may be associated with a low, but increased cancer risk.

Genes Included in NGS Panels

The following summarizes the function and disease association of major genes included in NGS panels. This summary is not comprehensive.

BRCA1 and BRCA2 Variants

BRCA1 and BRCA2 germline variants are associated with hereditary breast and ovarian cancer syndrome, which is associated most strongly with increased susceptibility to breast cancer at an early age, bilateral breast cancer, male breast cancer, ovarian cancer, cancer of the fallopian tube, and primary peritoneal cancer. BRCA1 and BCRA2 variants are also associated with increased risk of other cancers, including prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer.

APC Variants

APC germline variants are associated with familial adenomatous polyposis (FAP) and attenuated FAP. FAP is an autosomal dominant colon cancer predisposition syndrome characterized by hundreds to thousands of colorectal adenomatous polyps and accounts for about 1% of all colorectal cancers (CRCs).

ATM Variants

ATM is associated with the autosomal recessive condition ataxia-telangiectasia. This condition is characterized by progressive cerebellar ataxia with onset between the ages of one and four years, telangiectasias of the conjunctivae, oculomotor apraxia, immune defects, and cancer predisposition, particularly leukemia and lymphoma.

BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C Variants

BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes in the Fanconi anemia/BRCA pathway. Variants in these genes are estimated to confer up to a four-fold increase in the risk of breast cancer. This pathway is also associated with a higher risk of ovarian cancer and, less often, pancreatic cancer.

BMPR1A and SMAD4 Variants

BMPR1A and SMAD4 are genes mutate in juvenile polyposis syndrome and account for 45% to 60% of cases of juvenile polyposis syndrome. Juvenile polyposis syndrome is an autosomal dominant disorder that predisposes to the development of polyps in the gastrointestinal tract. Malignant transformation can occur, and the risk of gastrointestinal cancer has been estimated from 9% to 50%.

CHEK2 Variants

CHEK2 gene variants confer an increased risk of developing several different types of cancer, including breast, prostate, colon, thyroid, and kidney. CHEK2 regulates the function of the BRCA1 protein in DNA repair and has been associated with familial breast cancers.

CDH1 Variants

CDH1 germline variants are associated with lobular breast cancer in women and with hereditary diffuse gastric cancer (DGC). The estimated cumulative risk of gastric cancer for CDH1 variant carriers by age 80 years is 70% for men and 56% for women. CDH1 variants are associated with a lifetime risk of 39% to 52% of lobular breast cancer.

EPCAM, MLH1, MSH2, MSH6, and PMS2 Variants

EPCAM, MLH1, MSH2, MSH6, and PMS2 are mismatch repair genes associated with Lynch syndrome (hereditary nonpolyposis CRC). Lynch syndrome is estimated to cause 2% to 5% of all colon cancers. Lynch syndrome is associated with a significantly increased risk of several types of cancer-colon cancer (60%-80% lifetime risk), uterine/endometrial cancer (20%-60% lifetime risk), gastric cancer (11%-19% lifetime risk), and ovarian cancer (4%-13% lifetime risk). The risks of other types of cancer, including the small intestine, hepatobiliary tract, upper urinary tract, and brain, are also elevated.

MUTYH Variants

MUTYH germline variants are associated with an autosomal recessive form of hereditary polyposis. It has been reported that 33% and 57% of patients with clinical FAP and attenuated FAP, respectively, who are negative for variants in the APC gene, have MUTYH variants.

PALB2 Variants

PALB2 germline variants are associated with an increased risk of pancreatic and breast cancer. Familial pancreatic and/or breast cancer due to PALB2 variants are inherited in an autosomal dominant pattern.

PTEN Variants

PTEN variants are associated with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, and Proteus syndrome. CS is characterized by a high-risk of developing tumors of the thyroid, breast, and endometrium. Affected persons have a lifetime risk of up to 50% for breast cancer, 10% for thyroid cancer, and 5% to 10% for endometrial cancer.

STK11 Variants

STK11 germline variants are associated with Peutz-Jeghers syndrome, an autosomal dominant disorder, with a 57% to 81% risk of developing cancer by age 70, of which gastrointestinal and breast cancers are the most common.

TP53 Variants

TP53are associated with Li-Fraumeni syndrome. People with TP53variants have a 50% risk of developing any of the associated cancers by age 30 and a lifetime risk up to 90%, including sarcomas, breast cancer, brain tumors, and adrenal gland cancers.

NF1 Variants

Neurofibromin 1 encodes a negative regulator in the ras signal transduction pathway. Variants in the NF1 gene have been associated with neurofibromatosis type 1, juvenile myelomonocytic leukemia, and Watson syndrome.

RAD51D Variants

RAD51D germline variants are associated with familial breast and ovarian cancers.

CDK4 Variants

Cyclin-dependent kinase-4 is a protein-serine kinase involved in cell cycle regulation. Variants in this gene are associated with a variety of cancers, particularly cutaneous melanoma.

CDKN2A Variants

Cyclin-dependent kinase inhibitor 2A (CDKN2A) encodes proteins that act as multiple tumor suppressors through their involvement in 2 cell cycle regulatory pathways: the p53 pathway and the RB1 pathway. Variants or deletions in CDKN2Aare frequently found in multiple types of tumor cells. Germline variants in CDKN2A have been associated with the risk of melanoma, along with pancreatic and central nervous system cancers.

RET Variants

RET encodes a receptor tyrosine kinase; variants in this gene are associated with multiple endocrine neoplasia syndromes (types IIA and IIB) and medullary thyroid carcinoma.

SDHA, SDHB, SDHC, SDHD, and SDHAF2 Variants

SDHA, SDHB, SDHC, SDHD, and SDHAF2 gene products are involved in the assembly and function of one component of the mitochondrial respiratory chain. Germline variants in these genes are associated with the development of paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and a PTEN-negative Cowden-like syndrome.

TMEM127 Variants

Transmembrane protein 127 (TMEM127) germline variants are associated with the risk of pheochromocytomas.

VHL Variants

VHL germline variants are associated with Hippel-Lindau syndrome, an autosomal dominant familial cancer syndrome. This syndrome is associated with various malignant and benign tumors, including central nervous system tumors, renal cancers, pheochromocytomas, and pancreatic neuroendocrine tumors.

FH Variants

Fumarate hydratase variants are associated with renal cell and uterine cancers.

FLCN Variants

Folliculin acts as a tumor suppressor gene; variants in this gene are associated with the autosomal dominant Birt-Hogg-Dube syndrome, which is characterized by hair follicle hamartomas, kidney tumors, and CRC.

MET Variants

MET is a proto-oncogene that acts as the hepatocyte growth factor receptor. METvariants are associated with hepatocellular carcinoma and papillary renal cell carcinoma.

MITF Variants

Microphthalmia-associated transcription factor (MITF) is a transcription factor involved in melanocyte differentiation. MITF variants lead to several auditory-pigmentary syndromes, including Waardenburg syndrome type 2 and Tietze syndrome. MITF variants are also associated with melanoma and renal cell carcinoma.

TSC1 Variants

Tuberous sclerosis 1 and tuberous sclerosis 2 encode the proteins hamartin and tuberin, which are involved in cell growth, differentiation, and proliferation. Variants in these genes are associated with the development of tuberous sclerosis complex, an autosomal dominant syndrome characterized by skin abnormalities, developmental delay, seizures, and multiple types of cancers, including central nervous system tumors, renal tumors (including angiomyolipomas, renal cell carcinomas), and cardiac rhabdomyomas.

XRCC2 Variants

XRCC2 encodes proteins thought to be related to the RAD51 protein product that is involved in DNA double-stranded breaks. Variants may be associated with Fanconi anemia and breast cancer.

FANCC Variants

Fanconi anemia complementation group C is one of several DNA repair genes that mutate in Fanconi anemia, which is characterized by bone marrow failure and a high predisposition to multiple types of cancer

AXIN2 Variants

AXIN2 variants are associated with FAP syndrome, although the phenotypes associated with AXIN2 variants do not appear to be well-characterized.

Hereditary Cancer and Cancer Syndromes

Genetic testing for breast and ovarian cancer syndromes, single nucleotide variants related to breast cancer, and hereditary breast cancer are addressed in separate medical policies.

Genetic testing for Li-Fraumeni syndrome is addressed in a separate medical policy..

CS is a part of PHTS and is the only PHTS disorder associated with a documented predisposition to malignancies. Genetic testing for CS is addressed in a separate medical policy.

Hereditary Diffuse Gastric Cancer

Hereditary DGC is an autosomal dominant trait. Up to 50% of familial cases may be caused by variants in the CDH1 gene. In kindred families with CDH1-positive hereditary DGC, the risk of developing DGC is as high as 80% by 80 years of age. Other candidate genes include CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. Guidelines from the International Gastric Cancer Linkage Consortium have proposed genetic testing in families with 2 or more patients with gastric cancer at any age, in individuals with DGC before the age of 40, or in families with diagnoses of both DGC and invasive lobular cancer. Because of the high lifetime risk, prophylactic total gastrectomy between the ages of 20 and 30 is usually advised.

Hereditary Colon Cancer Syndromes

Genetic testing for hereditary colon cancer syndromes are addressed in a separate medical policy. Hereditary colon cancer syndromes are thought to account for approximately 10% of all CRCs. Another 20% have a familial predilection for CRC without a clear hereditary syndrome identified.^1, The hereditary CRC syndromes can be divided into the polyposis and nonpolyposis syndromes. Although there may be polyps in the nonpolyposis syndromes, they are usually less numerous; the presence of ten colonic polyps is used as a rough threshold when considering genetic testing for a polyposis syndrome.^2, The polyposis syndromes can be further subdivided by polyp histology, which includes the adenomatous (FAP, attenuated FAP, MUTYH-associated) and hamartomatous (juvenile polyposis syndrome, Peutz-Jeghers syndrome, PHTS) polyposis syndromes. The nonpolyposis syndromes include Lynch syndrome.

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. 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 these tests.

Related Policies

• Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (Policy #012 in the Pathology Section)
• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes (Policy #015 in the Pathology Section)
• Genetic Testing for Li-Fraumeni Syndrome (Policy #108 in the Pathology Section)
• Moderate Penetrance Variants Associated with Breast Cancer in Individuals at High Breast Cancer Risk (Policy #118 in the Pathology Section)
• Use of Common Genetic Variants to Predict Risk of Nonfamilial Breast Cancer (Policy #063 in the Medicine Section)
• Genetic Testing for PTEN Hamartoma Tumor Syndrome (Policy #121 in the Pathology Section)
• General Approach to Evaluating the Utility of Genetic Panels (Policy #083 in the Pathology Section)

o The Individual has either recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer; and
o The Individual has either not been previously tested using the same NGS test for the same primary diagnosis of cancer or repeat testing using the same NGS test only when a new primary cancer diagnosis is made by the treating physician; and
o The Individual has decided to seek further cancer treatment (e.g., therapeutic chemotherapy).

o Food & Drug Administration (FDA) approval or clearance as a companion in vitro diagnostic; and,
o an FDA-approved or -cleared indication for use in that individual’s cancer; and,
o results provided to the treating physician for management of the individual using a report template to specify treatment options.

· ovarian or breast cancer; and
· a clinical indication for germline (inherited) testing for hereditary breast or ovarian cancer; and
· a risk factor for germline (inherited) breast or ovarian cancer; and
· was not been previously tested with the same germline test using NGS for the same germline genetic content.

· Food and Drug Administration (FDA) approval or clearance; and
· results provided to the treating physician for management of the individual using a report template to specify treatment options

· any cancer diagnosis; and
· a clinical indication for germline (inherited) testing of hereditary cancers; and
· a risk factor for germline (inherited) cancer; and
· has not been previously tested with the same germline test using NGS for the same germline genetic content.

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.

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 Table1). 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 terminology¾“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”¾to 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.

[RATIONALE: This policy was created in 2013 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through August 12, 2019.

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.

Cancer Susceptibility Panels

Cancer susceptibility panels may be either diagnostic or prognostic.

Clinical Context and Test Purpose

The purpose of diagnostic testing symptomatic patients for genetic or heritable pathogenic variants is to establish a molecular diagnosis defined by the presence of a known pathologic variant(s). For genetic testing, a symptomatic individual is defined as one with a clinical phenotype that correlates with a known pathologic variant but who has not yet developed a malignancy. The criteria under which testing for genetic cancer susceptibility may be considered clinically useful are as follows:

• An association of the marker with the disorder has been established;
• Symptoms of the disease are present;
• A definitive diagnosis cannot be made based on history, physical examination, pedigree analysis, and/or standard diagnostic studies or tests; and
• The clinical utility of diagnosis has been established (eg, by demonstrating that a definitive diagnosis will lead to changes in the clinical management of the condition, changes in surveillance, or changes in reproductive decision making, and these changes will lead to improved health outcomes).

• An association of the marker with the natural history of the disease has been established; and
• The clinical utility of identifying the variant has been established (eg, by demonstrating that testing will lead to changes in the clinical management of the condition or changes in surveillance).

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

Patients

The relevant population of interest are patients being evaluated for clinical signs or symptoms that may be associated with a risk for the presence of a heritable cancer variant (diagnostic testing) or have a family member(s) diagnosed with heritable cancer(s) (prognostic testing).

Intervention

The test being considered is a cancer susceptibility panel.

Comparator

The following test is currently being used to make decisions about managing cancer susceptibility: individual gene variant testing.

Outcomes

The outcomes of interest are sensitivity and specificity, positive and negative predictive value, and reductions in morbidity and mortality.

Timing

Follow-up varies by whether testing is diagnostic or prognostic.

Setting

These tests are offered commercially through various manufacturers and institutions.

Technically Reliable

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 published literature provides no guidance on the assessment of the clinical validity of panel testing for cancer susceptibility with next-generation sequencing (NGS), and the usual approach to establishing the clinical validity of genetic testing is difficult to apply to panel testing.

Although it may be possible to evaluate the clinical validity of the sequencing of individual genes found on these panels, the clinical validity of NGS for cancer susceptibility panels, which include variants associated with unknown or variable cancer risk, are of uncertain clinical validity.

For genetic susceptibility to cancer, clinical validity can be considered at the following levels:

1. Does a positive test identify a person as having an increased risk of developing cancer?
2. If so, how high is the risk of cancer associated with a positive test?

The likelihood that someone with a positive test result will develop cancer is affected not only by the presence of the gene variant but also by other modifying factors that can affect the penetrance of the variant (eg, environmental exposures, personal behaviors) or by the presence or absence of variants in other genes.

Susswein et al (2016) reviewed the genetic test results and clinical data from a consecutive series of 10030 patients referred for evaluation by a hereditary cancer panel between August 2013 and October 2014.^3, Personal and family histories of cancer were obtained, and patients categorized as having breast, colon, stomach, ovarian, endometrial, or pancreatic cancer; other cancer types were not singled out for analysis. Patients with breast and ovarian cancers were stratified according to previous BRCA1and BRCA2 genetic testing. Patients with colon or stomach cancers were combined because of the small number of patients with stomach cancers. Eight multigene cancer panels comprising combinations of 29 genes were included. Genetic variants were classified as pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, or benign or variants according to the 2007 guidelines from the American College of Medical Genetics and Genomics.^4,

Genes included in the panels were grouped into 3 risk categories based on penetrance data available in 2012, as follows:

• high risk: APC, BMPR1A, BRCA1, BRCA2, CDH1, CDKN2A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53, and VHL
• moderate risk: ATM, CHEK2, and PALB2
• increased but less well-defined risk: AXIN2, BARD1, BRIP1, CDK4, FANCC, NBN, RAD51C, RAD51D, and XRCC2.

Individuals with colon/stomach cancer had the highest yield of positive results(14.8% [113/764]), the majority of which were in well-established colon cancer genes:MLH1, MSH2, MSH6, PMS2, EPCAM, MUTYH, APC, PTEN, and STK11. However, 28.2% (35/124) were observed in genes not considered classical for gastrointestinal cancers: BRCA1,BRCA2, CHEK2, ATM, PALB2, BRIP1, and RAD51D. BRCA1 and BRCA2 accounted for 9.7% (12/124) of positive variants identified in individuals diagnosed with colon cancer. The Lynch syndrome/colorectal cancer (CRC) panel (GeneDx), containing MLH1, MSH2, MSH6,PMS2, EPCAM, APC, and MUTYH, had the highest yield (13.7% overall; 17.6% among affected individuals). The panel’s high yield was likely a result of the well-established association of all genes on this panel with CRC and the specific clinical history or tumor characteristics (microsatellite instability and/or immunohistochemistry)that prompted providers to order this focused panel.

The breast cancer high-risk panel containing BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53 had the lowest yield (3.8% overall, 4.2% among individuals with breast cancer). The highest VUS frequency was observed with the largest panel (29 genes), and the lowest VUS rate was observed with the high-risk breast cancer panel with 6 genes. For patients with breast cancer, 9.7% (320/3315) of women without prior BRCA1 and BRCA2 testing were found to carry a pathogenic or likely pathogenic variant, of which BRCA1 and BRCA2 accounted for 39.1%. Other high-risk genes (including TP53, PTEN, and CDH1) accounted for 5.8% (19/330), and 5.2% (17/330) of the patients carried the Lynch syndrome genes. Moderate and less well-defined risk genes accounted for 50.0% (165/330) of all positive results among women with breast cancer. Of women with ovarian cancer without previous BRCA1 and BRCA2 testing, 13.4% (89/663) had variants, of which BRCA1 and BRCA2 accounted for 50.5%, Lynch syndrome genes for 14.3%, and moderate or less well-defined risk genes for 33.0%. Of the 453 women with endometrial cancer, the yield for identifying a variant was 11.9% (n=54): 7.3% (n=33) of these were within a Lynch gene, most commonly MSH6; CHEK2 was positive in 7%, with an overall frequency of 1.5%; and 6 positive results were identified in BRCA1 and BRCA2, 10.9% (6/55) of all positive variants identified.

Among 190 pancreatic cancer patients, the yield for identifying a variant was 10.5% (n=20), most commonly identified in ATM (40.0% [8/20]), BRCA2 (25.0% [5/20]), and PALB2 (15.0% [3/20]). Of 901 patients with positive results, 28 (3.1%) had more than 1 positive finding, reflecting 0.3% (28/10030) of the total testing population; 5 had positive results in 2 highly penetrant genes; 12 had 1 positive result in a high-risk gene, and 1 in a gene with moderate or unknown risk; and 11 had 2 positive findings in genes with moderate or unknown risk.

Six (33%) of the 18 patients with positive findings in TP53 did not meet classic Li-Fraumeni syndrome, Li-Fraumeni-like syndrome, 2009 Chompret, or National Comprehensive Cancer Network guideline criteria for TP53 testing, resulting in a frequency of 0.06% (6/9605) unanticipated positive results. Four patients had a positive CDH1 result, two of whom did not meet the International Gastric Cancer Linkage Consortium testing criteria, resulting in a frequency of 0.02% (2/8708) positive CDH1 results. In summary, among patients with specific cancers, yields were 9.7%, 13.4%, and 14.8% in patients with breast, ovarian, and colon/stomach cancers, respectively. Approximately 5.8% of positive results among women with breast cancer were in highly penetrant genes other than BRCA1 and BRCA2. The yield in Lynch syndrome genes among breast cancer patients was 0.5% (17/3315), higher than a published upper estimate of the prevalence of Lynch among the general population (0.2%). More than a quarter of patients with colon cancer tested positive for genes not considered to be classic CRC genes. Over 11% of the positive findings among women with endometrial cancer were in BRCA1 and BRCA2. A small number of patients whose personal and family histories were not suggestive of Li-Fraumeni syndrome were positive for pathogenic variants in the TP53 gene.

LaDuca et al (2014) reported on the clinical and molecular characteristics of 2079 patients who underwent panel testing with BreastNext, OvaNext, ColoNext, or CancerNext (Ambry Genetics).^5, Most (94%) patients had a personal history of cancer or adenomatous polyps, and in 5% of cases, the proband was reported to be clinically unaffected. A total of 2079 cases were included: 874 BreastNext, 222 OvaNext, 557 ColoNext, and 425 CancerNext. The positive and inconclusive rates for the panels were, respectively, 7.4% and 20% for BreastNext, 7.2% and 26% for OvaNext, 9.2% and 15% for ColoNext, and 9.6% and 24% for CancerNext.

Hereditary Breast and Ovarian Cancer

O’Leary et al (2017) reported on 1085 cases with non-BRCA1 or BRCA2 breast cancer referred to a commercial laboratory that were found to have a pathogenic or likely pathogenic variant.^6, The cases were divided into three groups based on the panel requested by the ordering physician: genes primarily associated with breast cancer (group A), genes associated with breast, gynecologic, and gastrointestinal cancer types (group B), and large comprehensive panels (group C). The proportion of positive finding in genes with breast management guidelines was inversely related to the size of the panel: 97.5% in group A, 63.6% in group B, and 50% in group C. Conversely, more positive findings and unexpected findings (there was no family history) were identified in actionable non breast cancer genes as the size of the panel increased. VUS rates also increased as the size of the panel increased, with 12.7% VUS in group A, 31.6% in group B, and 49.6% in group C.

Couch et al (2017) evaluated 21 genetic predisposition genes for breast cancer in a sample of 38326 white women with breast cancer who received any one of a variety of genetic test panels (Ambry Genetics).^7, The frequency of pathogenic variants was estimated at 10.2%. After the exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, TP53), five additional genes with variants classified as pathogenic by ClinVar were associated with high or moderately increased risk of breast cancer (see Table 3). Notably, of the various panels included in this study, only the BRCAplus panel is limited to the set of genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN) that were associated with breast cancer in women of European descent.

Table 1. Moderate-to-High Risk Non-BRCA1 and BRCA2, Nonsyndromic Genes Associated With Breast Cancer

Gene	Odds Ratio	95% Confidence Interval	Risk Category
ATM	2.78	2.22 to 3.62	Moderate
BARD1	2.16	1.31 to 3.63	Moderate
CHEK2	1.48	1.31 to 1.67	Moderate
PALB2	7.46	5.12 to 11.19	High
RAD51D	3.07	1.21 to 7.88	Moderate

Other studies have assessed the prevalence of pathogenic variants among patients with breast cancer who were referred for genetic testing, using a panel of 25 genes associated with inherited cancer predisposition (Myriad Genetics). A study by Buys et al (2017) included over 35000 women with breast cancer who were assessed with the Myriad 25-gene panel.^8, Pathogenic variants were identified in 9.3% of the women tested. Nearly half of those variants were in the BRCA1 or BRCA2 genes. The remaining variants were found in other breast cancer genes, Lynch syndrome genes, and other panel genes. The VUS rate was 36.7%

A similar study by Langer et al (2016) evaluated the frequency of pathogenic variants identified with the 25-gene panel (Myriad Genetics) in 3088 patients with a personal history of ovarian cancer who were referred for testing.^9, Pathogenic or likely pathogenic variants were identified in 419 (13.6%) patients, of whom 7 patients had variants in 2 different genes. Nearly all patients (99.2%) met National Comprehensive Cancer Network guidelines for hereditary breast and ovarian cancer testing (78.4%), Lynch syndrome testing (0.3%), or both (20.5%). Of the 419 patients with pathogenic or likely pathogenic variants, 277 (65%) were identified in BRCA1 or BRCA2: 33 (7.8%) in Lynch syndrome-associated genes (PMS2, MSH6, MLH1, MSH2), and 26.8% in genes with a low-to-moderate increase in cancer risk (ATM, BRIP1, CHEK2, RAD51C, PALB2, NBN), or one of 6 other genes (<1% each). One or more VUS were reported in 1141 (36.9%) of patients.

Tung et al (2015) included 2 cohorts: 1781 patients referred for commercial testing for BRCA1 and BRCA2 variants and whose samples were consecutively submitted to Myriad between November 2012 and April 2013 (cohort 1), and 377 DNA samples from patients who were referred to Beth Israel Deaconess Medical Center for genetic testing between 1998 and 2013 and had previously tested negative for BRCA1 and BRCA2 (cohort 2).^10, Variants were identified in 16 genes, with the most frequent being BRCA1, BRCA2, CHEK2, ATM, and PALB2.

Colorectal Cancer

Hansen et al (2017) published a retrospective analysis using multigene panel testing to identify genetic causes for increased CRC risk.^11, A custom gene panel targeting 112 genes, including both well-known and candidate CRC susceptibility genes, was designed, and variants were validated by Sanger sequencing. DNA samples from 274 familial CRC patients who fulfilled the Amsterdam I/II and/or the Revised Bethesda guidelines were included. All had previously been screened for variants in 1 or more of the MMR genes (MLH1, MSH2, MSH6, PMS2) without any pathogenic findings. In well-known cancer susceptibility genes, 17 pathogenic variants and 19 VUS were identified. Thirty-seven potentially pathogenic variants in candidate CRC susceptibility genes were also identified. Clinical correlations were not available.

In an industry-sponsored study, Cragun et al (2014) reported on the prevalence of clinically significant variants and VUS among patients who underwent ColoNext panel testing.^12,For the period included in the study (March 2012-March 2013), the ColoNext test included the MLH1, MSH2, MSH6, PMS2, EPCAM, BMPR1, SMAD4, STK11, APC, MUTYH, CHEK2, TP53, PTEN, and CDH1 genes. Alterations were classified as follows: (1) pathogenic variant; (2) variant, likely pathogenic; (3) variant, unknown significance; (4) variant, likely benign; and (5) benign. Data were analyzed for 586 patients whose ColoNext testing results and associated clinical data were maintained in a database by Ambry Genetics. Sixty-one (10.4%) patients had genetic alterations consistent with pathogenic variants or likely pathogenic variants; after 8 patients with only CHEK2 or 1 MUTYH variant were removed, 42 (7.2%) patients were considered to have actionable variants. One hundred eighteen (20.1%) patients had at least 1 VUS, including 14 patients who had at least 1 VUS in addition to a pathologic variant. Of the 42 patients with a pathologic variant, most (30 [71%] patients) met National Comprehensive Cancer Network guidelines for syndrome-based testing, screening, or diagnosis, based on the available clinical and family history. The authors noted “The reality remains that syndrome based testing would have been sufficient to identify the majority of patients with deleterious variants. Consequently, the optimal and most cost-effective use of panel-based testing as a first-tier test vsa second-tier test (i.e. after syndrome-based testing is negative), remains to be determined.”

Section Summary: Clinically Valid

Clinical validity studies have studied mixed populations; high-risk individuals due to clinical presentation or family history as well as cancer-affected persons with or without prior variant testing. Most studies have been retrospective. These studies have reported on the frequency with which well-known cancer susceptibility variants are identified using large panels and variably have reported the VUS rate. VUS rates increased in proportion with panel size, reaching nearly 50% for large gene panels.

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 randomized controlled trials.

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.

The following criteria can be used to evaluate the clinical utility of cancer susceptibility panel testing:

• Does panel testing offer substantial advantages in efficiency compared with sequential analysis of individual genes?
• Is decision making based on potential results of panel testing well-defined?
  • Do positive results on panel testing result in changes in cancer susceptibility that are clinically important?
  • Does this change in cancer susceptibility lead to changes in management that result in health outcome benefits for the patient being tested?
• Is the impact of ancillary information provided by panel testing well-defined?
  • What is the probability that ancillary information leads to further testing or management changes that may have either a positive or a negative impact on the patient being tested?

On the other hand, identifying variants that have intermediate or low penetrance is of limited clinical utility. Clinical management guidelines for patients found to have one of these variants are not well-defined. Also, there is a potential for harm, in that the diagnosis of an intermediate- or low-risk variant may lead to undue psychological stress and unnecessary prophylactic surgical intervention.

Idos et al (2018) conducted a prospective study that enrolled 2000 patients who had been referred for genetic testing at 1 of 3 academic medical centers (see Table 2).^13, Patients underwent differential diagnosis by a genetic clinician prior to cancer panel testing for 25 or 28 genes associated with breast or ovarian cancer, Lynch syndrome, and genes associated with gastric, colon, or pancreatic cancer. Results of the study are shown in Table3. Twelve percent of the patients were found to have a pathogenic variant, of which 66% was anticipated by the genetic clinician and 34% which were not anticipated. Most of the unanticipated results were in moderate to low penetrance genes. Thirty-four percent of the patients had a VUS and 53% of patients had benign results. Prophylactic surgery was performed more frequently in patients with a pathogenic variant (16%) compared to patients with a benign (2.4%) or unknown (2.3%) variant. Limitations in relevance and design and conduct are shown in Tables 4 and 5. Information on the actions associated with low to moderate penetrance genes were not reported. One concern with large panels is the increase in VUS. Having a VUS did not increase distress or uncertainty or diminish a positive experience of the testing in this study, and there was no increase in prophylactic surgery in patients with a VUS. However, all patients had received genetic counseling at an academic medical center regarding the outcomes of testing and this study may not be representative of community practice. In addition, a threshold for testing of 2.5% on a risk prediction model is a lower threshold than what is typically recommended. Patients with a positive result were more likely to encourage relatives to undergo testing. Longer-term follow-up for clinical outcomes is ongoing.

Table 2. Study Characteristics

Study	Study Population	Design	Comparator	Outcomes	Blinding of Assessors	Follow-up
Idos et al (2018)13,	2,000 patients who underwent a multi-gene cancer panel testa	Prospective	Differential diagnosis by a genetic clinician	Post-test survey of decisions and attitudes	No	1,573 surveys were returned at a median of 13 mo after the genetic test

^a Patients met genetic testing guidelines or had at least a 2.5% risk of cancer on a risk prediction model. Seventy-three percent had a personal history of cancer. Reasons for genetics referral included cancer diagnosis < 50 years of age, > 2 close relatives with cancer, > 1 family member with cancer at < 50 years of age, or history of multiple cancers.

Table 3. Study Results

Study	Initial N	Final N	Clinically Anticipated n (%)	Test Results not Clinically Anticipated n (%)	Outcome n (%)			P-value Pathogenic vs VUS
					Pathogenic	VUS	Negative
Idos et al (2018)13, Overall	2000		160/242 (66)	82/142 (34)	242 (12)a	689 (34)	1,069 (53)
Prophylactic surgery		62			30 (16.0)	12 (2.3)	20 (2.4)
Distress score (0 to 30) -mean (SD)		1,248			6.1 (6.04)	2.1 (4.2)	1.7 (3.5)	<0.001
Uncertainty (0 to 45) mean (SD)		1,223			11.4 (8.8)	7.4 (7.8)	6.3 (7.1)	<0.001
Positive experiences (0 to 20) mean (SD)		1,213			9.7 (5.1)	11.8 (6.3)	12.1 (6.5)	<0.001

SD: standard deviation; VUS: variant of uncertain significance.

^a31% had a variant in BRCA1/BRCA2, 16% had a variant associated with Lynch syndrome, 18% had a pathogenic MUTYH variant, and 8% had pathogenic variants in APC. Other genes included TP53, CHEK2, ATM, PALB2, BRIP1, RAD51C, BARD1, NBN, CDH1, and CDKN2A.

Table 4. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Idos et al (2018)13,	4. The population included patients down to 2.5% of risk on a risk prediction model.			1. The outcomes were patient-reported experience	1. Follow-up is continuing for clinical outcomes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Idos et al (2018)13,		1. Blinding not described			1. Surveys were completed by 69% of patients at 3 mo and 57% at 12 mo

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).

^bBlinding key: 1. Not blinded to results of reference or other comparator tests.

^cTest Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.

^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.

^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Lumish et al (2017) evaluated the impact of hereditary breast and ovarian cancer gene panel testing in 232 patients who had undergone gene panel testing after discussion with a genetic counselor.^14,From this sample, 129 patients had a personal history of cancer (11 with a pathogenic or likely pathogenic variant, 14 with a VUS, 104 with normal test results) and 103 had a family history of cancer (14 with a pathogenic or likely pathogenic variant, 20 with a VUS, 69 with normal test results). The greatest impact of test results was for the 14 patients with a family history of breast or ovarian cancer who received a positive (pathogenic or likely pathogenic) test result, leading to greater distress and more frequent screening in 13 patients and prophylactic surgery in 1. Positive test results for the 11 patients with a personal history of cancer influenced their decision about the type of surgery for 4 (36.4%) patients. For the 20 patients with a family history of cancer and a VUS result, distress increased to an intermediate level, and 7 (35%) patients reported that their test result would impact the decision to have additional screening. The authors of this study noted that the VUS rate would increase with the number of genes in a panel and that the choice of a panel would need to optimize the chance of receiving results with clinical utility while minimizing the chance of results that have disutility and increase anxiety.

Eliade et al (2017) evaluated the clinical actionability of a multigene panel in a cohort of 583 patients with a family history of breast or ovarian cancer.^15, A pathogenic or likely pathogenic BRCA1 or BRCA2 variant was identified in 51 (9%) patients, and a pathogenic or likely pathogenic variant was identified in 10 other genes in the panel for 37 patients. The most frequently mutated genes were CHEK2 (n=12 [2%]), ATM (n=9 [1.5%]), and PALB2 (n=4 [0.6%]). The identification of a pathogenic/likely pathogenic variant in a high-risk gene or intwo genes led to a change in surveillance or prophylactic surgery. In patients with a positive finding in a moderate-risk gene, breast magnetic resonance imaging was recommended, while surveillance according to family history was recommended in patients with a negative finding. There was no change in management in the four women with a positive finding in a low-risk gene (BRIP1, BARD1, RAD50). Individuals with a negative finding could not be reassured, given the possibility of a pathogenic or likely pathogenic variant in an as-yet-undiscovered gene.

Rosenthal et al (2017) published an industry-sponsored study evaluating the clinical utility of a 25-gene pan-cancer panel.^16, The analysis included 252223 consecutive individuals, most of whom (92.8%) met testing criteria for hereditary breast and ovarian cancer and/or Lynch syndrome. Pathogenic variants (n=17340) were identified in 17000 (6.7%) patients; the most common pathogenic variants were BRCA1 and BRCA2 (42.2%), other breast cancer genes (32.9%), Lynch syndrome genes (13.2%), and ovarian cancer genes (6.8%). Among individuals who met only hereditary breast and ovarian cancer or Lynch syndrome testing criteria, half of the pathogenic variants found were genes other than BRCA1 and BRCA2 or Lynch syndrome genes, respectively. The study was limited by reliance on providers for personal and family cancer histories and by uncertainty regarding the exact cancer risk spectrum for each gene included on the panel.

Kurian et al (2014) evaluated the information from an NGS panel of 42 cancer-associated genes in women previously referred for clinical BRCA1 and BRCA2 testing after clinical evaluation of hereditary breast and ovarian cancer from 2002 to 2012.^17, The authors aimed to assess concordance of the results of the panel with prior clinical sequencing, the prevalence of potentially clinically actionable results, and the downstream effects on cancer screening and risk reduction. Potentially actionable results were defined as pathogenic variants that cause recognized hereditary cancer syndromes or have a published association with a 2-fold or greater relative risk of breast cancer compared with average-risk women. In total, 198 women participated in the study. Of these, 174 had breast cancer and 57 carried 59 germline BRCA1 and BRCA2 variants. Testing with the panel confirmed 57 of 59 of the pathogenic BRCA1 and BRCA2 variants; of the 2 others, one was detected but reclassified as a VUS, and the other was a large insertion that would not be picked up by NGS panel testing. Of the women who tested negative for BRCA1 and BRCA2 variants (n=141), 16 had pathogenic variants in other genes (11.4%). The affected genes were ATM (n=2), BLM (n=1), CDH1 (n=1), CDKN2A (n=1), MLH1 (n=1), MUTYH (n=5), NBN (n=2), PRSS1 (n=1), and SLX4 (n=2). Eleven of these variants had been previously reported in the literature and five were novel. Eighty percent of the women with pathogenic variants in the non-BRCA1 and -BRCA2 genes had a personal history of breast cancer. Overall, a total of 428 VUS were identified in 39 genes, among 175 patients. Six women with variants in ATM, BLM, CDH1, NBN, and SLX4 were advised to consider annual breast magnetic resonance imaging because of an estimated doubling of breast cancer risk, and six with variants in CDH1, MLH1, and MUTYH were advised to consider frequent colonoscopy and/or endoscopic gastroduodenoscopy (once every 1-2 years) due to estimated increases in gastrointestinal cancer risk. One patient with an MLH1 variant consistent with Lynch syndrome underwent risk-reducing salpingo-oophorectomy and early colonoscopy, which identified a tubular adenoma that was excised (she had previously undergone hysterectomy for endometrial carcinoma). No clinical outcomes associated with the recommendations were reported.

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.

Because the clinical validity of cancer susceptibility panel testing for inherited cancer syndromes has not been established, a chain of evidence cannot be constructed.

Section Summary: Clinically Useful

Data are lacking for the clinical utility of multigene panels for inherited cancer susceptibility panels. There are management guidelines for syndromes with high penetrance, which have clinical utility in that they inform clinical decision making and result in the prevention of adverse health outcomes. Clinical management recommendations for the inherited conditions associated with low-to-moderate penetrance are not standardized, and the clinical utility of genetic testing for these variants is uncertain and could potentially lead to harm. Also, high VUS rates have been reported with the use of these panels.

Summary of Evidence

For individuals who have a personal and/or family history suggesting an inherited cancer syndrome who receive NGS panel testing, the evidence includes reports describing the frequency of detecting variants in patients referred for panel testing. The relevant outcomes are overall survival, disease-specific survival, and test validity. The accuracy of NGS may be reduced in complex genomic regions, and the interpretation of the significance of the variant (ie, pathogenic, benign, or variants of uncertain significance) can differ between laboratories. Clinical validity studies have reported on the results of the frequency with which variants are identified. The rates of variants of uncertain significance for gene panels are significant and increase in proportion with panel size, reaching nearly 50% for large gene panels. Published data on clinical utility is lacking, and it is unknown whether the use of these panels improves health outcomes. Variants included in these panels are associated with varying levels of risk of developing cancer. Only some variants included on panels are associated with a high risk of developing a well-defined cancer syndrome for which there are established clinical management guidelines. Many panels include genetic variants considered to be of moderate or low penetrance, and clinical management recommendations for these genes are not well-defined. The lack of clinical management pathways for variants of uncertain significance increases the potential for harm. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

American Society of Clinical Oncology

The American Society of Clinical Oncology (2015) issued a policy statement on genetic and genomic testing for cancer susceptibility.^18, The update addressed the application of next-generation sequencing and confirmed that panel testing may also identify variants in genes associated with moderate or low cancer risks, variants in high-penetrance genes that would not have been evaluated based on the presenting personal or family history, and as variants of uncertain significance in a substantial proportion of patient cases. Further, the statement indicated there is little consensus as to which genes should be included on panels for cancer susceptibility testing.

National Comprehensive Cancer Network

National Comprehensive Cancer Network guidelines on genetic/familial high-risk assessment for breast and ovarian cancers (v.3.2019)^19, state the following on multigene testing:

• "Patients who have a personal or family history suggestive of a single inherited cancer syndrome are most appropriately managed by genetic testing for that specific syndrome. When more than one gene can explain an inherited cancer syndrome, then multi-gene testing may be more efficient and/orcost-effective.
• There may be a role for multi-gene testing in individuals who have tested negative (indeterminate) for a single syndrome, but whose personal or family history remains suggestive of an inherited susceptibility.
• As commercially available tests differ in the specific genes analyzed (as well as classification of variants and many other factors), choosing the specific laboratory and test panel is important.
• Multi-gene testing can include “intermediate” penetrant (moderate-risk) genes. For many of these genes, there are limited data on the degree of cancer risk and there are no clear guidelines on risk management for carriers of mutations. Not all genes included on available multi-gene test are necessarily clinically actionable.
• As is the case with high-risk genes, it is possible that the risks associated with moderate-risk genes may not be entirely due to that gene alone, but may be influenced by gene/gene or gene/environment interactions…. Therefore, it may be difficult to use a known mutation alone to assign risk for relatives.
• In many cases, the information from testing for moderate penetrance genes does not change risk management compared with that based on family history alone…."
• There is an increased likelihood of finding variants of unknown significance when testing for pathogenic/likely pathogenic variants in multiple genes.
• It is for these and other reasons that multigene testing is ideally offered in the context of professional genetic expertise for pre- and post-test counseling."

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2015) has recommended that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with one of several screening tools designed to identify a family history that may be associated with an increased risk for potentially harmful variants in breast cancer and susceptibility genes (BRCA1 or BRCA2).^21,Women with positive screening results should receive genetic counseling and if indicated after counseling, BRCA testing (grade B recommendation). The use of genetic cancer susceptibility panels was not specifically mentioned.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03688204	Clinical Implementation of a Polygenic Risk Score (PRS) for Breast Cancer: Impact on Risk Estimates, Management Recommendations, Clinical Outcomes, and Patient Perception	2,000	Sep 2025
Unpublished
NCT01850654	Ohio Colorectal Cancer Prevention Initiative: Universal Screening for Lynch Syndrome	3470	Jun 2018

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 Cancer Susceptibility Panels
Genetic Cancer Susceptibility Panels Using Next Generation Sequencing
Cancer Susceptibility Panels Using Next Generation Sequencing
Next Generation Sequencing, Genetic Cancer Susceptibility Panels
Ambry Genetics Hereditary Cancer Panel Tests
BreastNext
CancerNext
ColoNext
OvaNext
RenalNext
PGLNext
PancNext
TumorNext
ProstateNext
GYNplus
BRCAplus
GeneDx Hereditary Cancer Panel Tests
Breast and Ovarian Cancer Panel
Breast Cancer High/Moderate Risk Panel
Endometrial Cancer Panel
Lynch/ Colorectal Cancer High Risk Panel
Colorectal High Risk Cancer Panel
Pancreatic Cancer Panel
Comprehensive Cancer Panel
Genetic Panels, Cancer
High/Moderate Risk Panel
Colorectal and Polyposis Cancer Panel
Breast Cancer Panel
MSK-IMPACT Cancer Panel
Color Cancer Panel
Counsyl Reliant Cabcer Screen Panel
Mayo Clinic Colon Cancer Panel
U Washington BROCA Cancer Panel
BROCA Cancer Panel
U Washington ColoSeq Cancer Panel
ColoSeq Cancer Panel
myRisk Hereditary Cancer Panel Test

References:
1. Schrader K, Offit K, Stadler ZK. Genetic testing in gastrointestinal cancers: a case-based approach. Oncology (Williston Park). May 2012;26(5):433-436, 438, 444-436 passim. PMID 22730601.

2. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am. Oct 2009;18(4):687-703. PMID 19793575.

3. Susswein LR, Marshall ML, Nusbaum R, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. Aug 2016;18(8):823-832. PMID 26681312.

4. Richards CS, Bale S, Bellissimo DB, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. Apr 2008;10(4):294-300. PMID 18414213.

5. LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med. Nov 2014;16(11):830-837. PMID 24763289.

6. O'Leary E, Iacoboni D, Holle J, et al. Expanded gene panel use for women with breast cancer: identification and intervention beyond breast cancer risk. Ann Surg Oncol. Oct 2017;24(10):3060-3066. PMID 28766213.

7. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. Sep 01 2017;3(9):1190-1196. PMID 28418444.

8. Buys SS, Sandbach JF, Gammon A, et al. A study of over 35,000 women with breast cancer tested with a 25- gene panel of hereditary cancer genes. Cancer. May 15 2017;123(10):1721-1730. PMID 28085182.

9. Langer LR, McCoy H, Kidd J, et al. A study of patients with ovarian cancer tested with a 25-gene hereditary cancer panel. J Community Support Oncol. 2016;14(7):314-319.

10. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. Jan 1 2015;121(1):25-33. PMID 25186627.

11. Hansen MF, Johansen J, Sylvander AE, et al. Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome. Clin Genet. Oct 2017;92(4):405-414. PMID 28195393.

12. Cragun D, Radford C, Dolinsky JS, et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet. Dec 2014;86(6):510-520. PMID 24506336.

13. Idos GE, Kurian AW, Ricker C, et al. Multicenter prospective cohort study of the diagnostic yield and patient experience of multiplex gene panel testing for hereditary cancer risk. DOI: 10.1200/PO.18.00217 JCO Precision Oncology.

14. Lumish HS, Steinfeld H, Koval C, et al. Impact of panel gene testing for hereditary breast and ovarian cancer on patients. J Genet Couns. Oct 2017;26(5):1116-1129. PMID 28357778.

15. Eliade M, Skrzypski J, Baurand A, et al. The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget. Jan 10 2017;8(2):1957-1971. PMID 27779110.

16. Rosenthal ET, Bernhisel R, Brown K, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genet. Dec 2017;218-219:58-68. PMID 29153097.

17. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. Jul 1 2014;32(19):2001-2009. PMID 24733792.

18. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. Nov 1 2015;33(31):3660-3667. PMID 26324357.

19. National Comprehensive Cancer Network (NCCN). NCCN National Clinical Practice Guidelines in Oncology: Genetic/Familial High Risk Assessment: Breast and Ovarian. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed September 17, 2019.

20. National Comprehensive Cancer Network (NCCN). NCCN National Clinical Practice Guidelines in Oncology: Genetic/Familial High Risk Assessment: Colorectal. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed September 17, 2019.

21. U. S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA- related cancer in women: recommendation statement. Am Fam Physician. Jan 15 2015;91(2):Online. PMID 25591222.

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*

81432
81433
81435
81436
81437
81438
81445
81450
81455
81479
0048U
0049U