| Coverage Policy Manual | |
| Policy #: | 2015009 |
| Category: | Laboratory |
| Initiated: | April 2015 |
| Last Review: | November 2024 |
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| Genetic Test: Next-Generation Sequencing for Cancer Susceptibility Panels | |
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| Description: |
Commercially available cancer susceptibility gene panels can test for multiple variants associated with a specific type of cancer or can include variants associated with a wide variety of cancers. Some of these variants are associated with inherited cancer syndromes. The cancer type(s), as well as a cancer history involving multiple family members increase the clinical concern for the presence of a heritable genetic variant. It has been proposed that variant testing using next-generation sequencing (NGS) technology to analyze multiple genes at once (panel testing) can optimize genetic testing in these individuals compared with sequencing single genes.
Genetic testing for cancer susceptibility may be approached by a focused method that involves testing for gene(s) that may be the cause of the familial cancer. Panel testing with next-generation sequencing (NGS) involves evaluating sequence variants in multiple genes at once.
Multiple commercial companies and medical center laboratories offer genetic testing panels that use next generation sequencing methods for hereditary cancers. Next generation 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 that are of unclear clinical significance or findings that would not lead to changes in patient management.
Next Generation Sequencing Panels
Ambry Genetics offers the following panels:
BRCA Plus (BRCA1, BRCA2, STK11, PTEN, TP53, CDH1)
GYNPlus (BRCA1, BRCA2, PTEN, TP53, MLH1, MSH2, MSH6, EPCAM)
BreastNext (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, NF1, RAD51D)
OvaNext (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, NF1, RAD51D)
ColoNext (STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4)
PancNext (BRCA1, BRCA2, ATM, PALB2, STK1, TP53, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, CDKN2A)
PGLNext (NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL)
RenalNext (PTEN, TP53, MLH1, MSH2, MSH6, EPCAM, PMS2, SDHA, SDHB, SDHC, SDHD, VHL, FH, FLCN, MET, MITF, TSC1, TSC2)
Cancer Next (BRCA1, BRCA2, ATM, BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, PALB2, STK11, CHEK2, STK11, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4, NF1, RAD51D, CDK4, CDKN2A)
GeneDx offers a number of comprehensive cancer panels that use next generation sequencing. The following is a list of available tests from GeneDx and the genes offered in each panel:
Breast/Ovarian Cancer Panel (BRCA1, BRCA2, ATM, BARD1, BRIP1, NBN, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MLH1, MSH2, MSH6, EPCAM, PMS2, RAD51D, XRCC2, FANCC, AXIN2)
Breast Cancer High-Risk Panel (BRCA1, BRCA2, STK11, PTEN, TP53, CDH1)
Endometrial Cancer Panel (BRCA1, BRCA2, PALB2, CHEK2, PTEN, TP53, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2)
Lynch/Colorectal Cancer High-Risk Panel (MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC)
Colorectal Cancer High-Risk Panel (ATM, STK11, CHEK2, STK11, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, BMPR1A, SMAD4, XRCC2, AXIN2)
Pancreatic Cancer Panel (BRCA1, BRCA2, ATM, PALB2, STK11, TP53, MLH1, MSH2, MSH6, EPCAM, PMS2, APC, CDK4, CDKN2A, VHL, XRCC2)
Comprehensive Cancer Panel (BRCA1, BRCA2, ATM, BARD1, BRIP1, RAD51C, PALB2, STK11, CHEK2, PTEN, TP53, CDH1, MUTYH, MLH1, MSH2, MSH6, EPCAM, PMS2, BMPR1A, SMAD4, RAD51D, CDK4, CDKN2A, VHL, XRCC2, FANCC, AXIN2)
BeScreened-CRC (2 protein biomarkers + teratocarcinoma derived growth factor-1 genetic expression profiling (TDGF-1, Cripto-1)
Mayo Clinic also offers a hereditary colon cancer multigene panel analysis, which includes the genes in the Ambry Genetics ColoNext, with the addition of 2 other low-risk genes (MLH3 and AXIN2). The University of Washington offers the BROCA Cancer Risk Panel, which is a next generation sequencing panel that includes the following mutations: AKT1, APC, ATM, ATR, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK1, CHEK2, CTNNA1, FAM175A, GALNT12, GEN1, GREM1, HOXB13, MEN1, MLH1, MRE11A, MSH2 (+EPCAM), MSH6, MUTYH, NBN, PALB2, PIK3CA, PPM1D, PMS2, POLD1, POLE, PRSS1, PTEN, RAD50, RAD51, RAD51C, RAD51D, RET, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, TP53BP1, VHL, and XRCC2 (Washington Uo. BROCA, 2015). The University of Washington also offers the ColoSeq gene panel, which includes 19 genes associated with Lynch syndrome (LS, hereditary nonpolyposis colorectal cancer, HNPCC), familial adenomatous polyposis (FAP), MUTYH-associated polyposis, (hereditary diffuse gastric cancer (HDGC), Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, Muir-Torre syndrome, Turcot syndrome, and juvenile polyposis syndrome (JPS): AKT1, APC, BMPR1A, CDH1, EPCAM, GALNT12, GREM1, MLH1, MSH2, MSH6, MUTYH, PIK3CA, PMS2, POLE, POLD1, PTEN, SMAD4, STK11, and TP53 (Washington, Uo. ColoSeq, 2015).
Myriad Genetics (Salt Lake City, UT) offers the myRISK next-generation sequencing panel, which includes testing for the following genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF), CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53.
Fulgent Diagnostics offers the Breast Ovarian Cancer NGS Panel: BRCA1 and BRCA2, along with cadherin 1, type1, E-cadherin (epithelial) (CDH1); partner and localizer of BRCA2 (PALB2); phosphate and tensin homolog (PTEN); serine/threonine kinase 11 (STK11); and tumor protein p53 (TP53), among others.
Lucence offers the Liquid HALLMARK next-generation sequencing assay which tests for mutations in 80 genes, fusions in 10 genes, and somatic variants: ABL1, AKT1, ALK, APC, AR, ARAF, ATM, AXL-MBIP, BAT25, BAT26, BRAF, BRCA1, BRCA2, CCND1, CCND2, CDH1, CDK6, CDKN2A, CLIP1-LTK, CREBBP, CTNNB1, CTNNB1-PLAG1, DNAJB1-PRKACA, EGFR, ERBB2, ERCC2, ERG, ESR1, ETV1, ETV4, ETV5, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLI1, FLT3, GATA3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK1, JAK2, JAK3, KEAP1, KIT, KRAS, MAP2K1, MAP2K2, MAPK1, MED12, MET, MLH1, MONO27, MTOR, MYB-NFIB, MYC, NF1, NFE2L2, NOTCH1, NR21, NR24, NR27, NRAS, NRG1, NTRK1, NTRK2, NTRK3, PAX8-FOXO1, PAX8-PPARG, PD-L1, PDGFRA, PIK3CA, PIK3R1, PPP2R1A, PTEN, PTPN11, RAF1, RB1, RET, RHEB, RHOA, RIT1, ROS1, RSPO3, SF3B1, SLC45A3, SMAD4, SMO, SPOP, SSX2, STK11, TERT Promoter, TFE3, THADA, TMPRSS2, TP53, U2AF1, VHL
Genes Included in Next Generation Sequencing Panels
The following is a summary of the function and disease association of major genes included in the next generation sequencing panels. This is not meant to be a comprehensive list of all genes included in all panels.
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 germline variants are associated with 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.
ATM is associated with the autosomal recessive condition ataxia-telangiectasia. This condition is characterized by progressive cerebellar ataxia with onset between the ages of 1 and 4 years, telangiectasias of the conjunctivae, oculomotor apraxia, immune defects, and cancer predisposition, particularly leukemia and lymphoma.
BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes in the Fanconi anemia-BRCA pathway. Variations in these genes are estimated to confer up to a 4-fold increase in the risk for breast cancer. This pathway is also associated with a higher risk of ovarian cancer and, less often, pancreatic cancer.
BMPR1A and SMAD4 are genes mutated in juvenile polyposis syndrome (JPS) and account for 45% to 60% of cases of JPS. JPS 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 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 BRCA1 protein in DNA repair and has been associated with familial breast cancers.
CDH1 is a tumor suppressing gene located on chromosome 16q22.1 that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing hereditary diffuse gastric cancer (DGC) and lobular breast cancer. A diagnosis of HDGC can be confirmed by genetic testing, although 20% to 40% of families with suspected HDGC do not have a CDH1 variant on genetic testing. Pathogenic CDH1 variants have been described in Maori families in New Zealand, and individuals of Maori ethnicity have a higher prevalence of diffuse-type gastric cancer than non-Maori New Zealanders. 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 are mismatch repair genes associated with LS (HNPCC). LS is estimated to cause 2% to 5% of all colon cancers. LS is associated with a significantly increased risk of several types of cancer—colon cancer (60% to 80% lifetime risk), uterine/endometrial cancer (20% to 60% lifetime risk), gastric cancer (11% to 19% lifetime risk) and ovarian cancer (4%-13% lifetime risk). The risk of other types of cancer, including small intestine, hepatobiliary tract, upper urinary tract and brain, are also elevated.
MUTYH germline mutations 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 germline variants have been 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 are associated with PTEN hamartoma tumor syndrome, 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 germline variants are associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder, with a 57% to 81% risk of developing cancer by age 70, of which gastrointestinal and breast are the most common.
TP53 variants are associated with Li-Fraumeni syndrome. People with TP53 variants 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 cancer.
NF1 (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 germline variants have been associated with familial breast and ovarian cancer.
CDK4 (cyclin-dependent kinase-4) is a protein-serine kinase involved in cell cycle regulation. Variants in this gene have been associated with a variety of cancers, particularly cutaneous melanoma.
CDKN2A (cyclin-dependent kinase inhibitor 2A) 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 CDKN2A are frequently found in multiple types of tumor cells. Germline mutations in CDKN2A have been associated with risk of melanoma, along with pancreatic and central nervous system cancers.
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 gene products are involved in the assembly and function of a 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 (transmembrane protein 127) germline variants are associated with risk of pheochromocytomas.
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 (fumarate hydratase) variants are associated with renal cell and uterine cancers.
FLCN (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 colorectal cancer.
MET is a proto-oncogene that acts as the hepatocyte growth factor receptor. MET variants are associated with hepatocellular carcinoma and papillary renal cell carcinoma.
MITF (microphthalmia-associated transcription factor) 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 (tuberous sclerosis 1) and TSC2 (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 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 (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 are associated with familial adenomatous polyposis syndrome, although the phenotypes associated with AXIN2 variants do not appear to be well characterized.
Hereditary Cancer and Cancer Syndromes
Hereditary breast cancer. Breast cancer can be classified as sporadic, familial, or hereditary. Sporadic breast cancer accounts for 70% to 75% of cases and is thought to be due to nonhereditary causes. Familial breast cancer, in which there are more cases within a family than statistically expected, but with no specific pattern of inheritance, accounts for 15% to 25% of cases. Hereditary breast accounts for 5% to 10% of cases and is characterized by well-known susceptibility genes with apparently autosomal dominant transmission.
The “classic” inherited breast cancer syndrome is the hereditary breast and ovarian cancer [HBOC] syndrome, most of which are due to mutations in the BRCA1 and BRCA2 genes. Other hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS, associated with TP53 mutations), CS (associated with PTEN mutations), PJS (associated with STK11 mutations), hereditary diffuse gastric cancer, and possibly LS also predispose patients to varying degrees of risk for breast cancer. Other mutations and SNPs have also been associated with increased risk of breast cancer.
Mutations associated with breast cancer vary in their penetrance. Highly penetrant mutations in the BRCA1, BRCA2, TP53, and PTEN genes may be associated with a lifetime breast cancer risk ranging from 40% to 85%. Only about 5% to 10% of all cases of breast cancer are attributable to a highly penetrant cancer predisposition gene. In addition to breast cancer, mutations in these genes may also confer a higher risk for other cancers (Shannon, 2012).
Other mutations may be associated with intermediate penetrance and a lifetime breast cancer risk of 20% to 40% (e.g., CHEK2, APC, CDH-1). Low-penetrance mutations discovered in genome-wide association studies (e.g., SNPs), are generally common and confer a modest increase in risk, although penetrance can vary based on environmental and lifestyle factors.
An accurate and comprehensive family history of cancer is essential for identifying people who may be at risk for inherited breast cancer and should include a 3-generation family history with information on both maternal and paternal lineages. Focus should be on both the people with malignancies and also family members without a personal history of cancer. It is also important to document the presence of nonmalignant findings in the proband and the family, as some inherited cancer syndromes are also associated with other nonmalignant physical characteristics (e.g., benign skin tumors in CS).
Further discussion on the diagnostic criteria of HBOC will not be addressed in this policy. Criteria for a presumptive clinical diagnosis of LFS and CS have been established.
LFS. LFS has been estimated to be involved in approximately 1% of hereditary breast cancer cases. LFS is a highly penetrant cancer syndrome associated with a high lifetime risk of cancer. People with LFS often present with certain cancers (soft tissue sarcomas, brain tumors, adrenocortical carcinomas) in early childhood and have an increased risk of developing multiple primary cancers during their lifetime.
Classic LFS is defined by the following criteria:
The 2009 Chompret criteria for LFS / TP53 testing are as follows:
Classic criteria for LFS have been estimated to have a positive predictive value of 56%, and a high specificity, although the sensitivity is low at approximately 40% (Gonzalez, 2009). The Chompret criteria have an estimated positive predictive value of 20% to 35%, and when incorporated as part of TP53 testing criteria in conjunction with classic LFS criteria, substantially improve the sensitivity of detecting LFS. When the Chompret criteria are added to the classic LFS criteria, the sensitivity for detected patients with TP53 mutations is approximately 95%.
The National Comprehensive Cancer Network (NCCN) also considers women with early onset breast cancer (age of diagnosis younger than 30 years), with or without a family history of the core tumor types found in LFS, as another group in whom TP53 gene mutation testing may be considered. If the LFS testing criteria are met, NCCN guidelines recommend testing for the familial TP53 mutation if it is known to be present in the family. If it is not known to be present, comprehensive TP53 testing is recommended, i.e., full sequencing of TP53 and deletion/duplication analysis, of a patient with breast cancer. If the patient is unaffected, testing the family member with the highest likelihood of a TP53 mutation is recommended. If a mutation is found, recommendations for management of LFS, include increased cancer surveillance and, at an earlier age, possible prophylactic surgical management, discussion of risk of relatives, and consideration of reproductive options. NCCN guidelines also state that in the situation where a person from a family with no known familial TP53 mutation undergoes testing and no mutation is found, testing for other hereditary breast syndromes should be considered if testing criteria are met.
CS. CS is a part of the PTEN hamartoma tumor syndrome (PHTS) and is the only PHTS disorder associated with a documented predisposition to malignancies. Women with CS have a high risk of benign fibrocystic disease, and a lifetime risk of breast cancer estimated at 25% to 50%, with an average age of between 38 and 46 years at diagnosis. The PTEN mutation frequency in people meeting International Cowden Consortium criteria (Pilarski, 2004) for CS has been estimated to be approximately 80%. A presumptive diagnosis of PHTS is based on clinical findings; however, because of the phenotypic heterogeneity associated with the hamartoma syndromes, the diagnosis of PHTS is made only when a PTEN mutation is identified. Clinical management of breast cancer risk in patients with CS includes screening at an earlier age and possible risk-reducing surgery.
Hereditary ovarian cancer. The single greatest risk factor for ovarian cancer is a family history of disease. Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Ovarian cancer has been associated with LS, basal cell nevus (Gorlin) syndrome, and multiple endocrine neoplasia.
Hereditary colon cancer. Hereditary colon cancer syndromes are thought to account for approximately 10% of all colorectal cancers. Another 20% have a familial predilection for colorectal cancer without a clear hereditary syndrome identified (Schrader, 2012). The hereditary colorectal cancer 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 10 colonic polyps is used as a rough threshold when considering genetic testing for a polyposis syndrome (Hampel, 2009). The polyposis syndromes can be further subdivided by polyp histology, which includes the adenomatous (FAP, aFAP, and MUTYH-associated) and hamartomatous (JPS, PJS, PTEN hamartoma tumor syndrome) polyposis syndromes. The nonpolyposis syndromes include LS.
Identifying which patients should undergo genetic testing for an inherited colon cancer syndrome depends on family history and clinical manifestations. Clinical criteria are used to focus testing according to polyposis or nonpolyposis syndromes, and for adenomatous or hamartomatous type within the polyposis syndromes. If a patient presents with multiple adenomatous polyps, testing in most circumstances focuses on APC and MUTYH testing. Hamartomatous polyps could focus testing for mutations in the genes STK11/LKB1, SMAD4, BMPR1A, and/or PTEN.
Genetic testing to confirm the diagnosis of LS is usually performed on the basis of family history in those families meeting the Amsterdam criteria (Vasen, 1999) who have tumor microsatellite instability (MSI) by immunohistochemistry on tumor tissue. Immunohistochemical testing helps identify which of the 4 MMR genes (MLH1, MSH2, MSH6, PMS2) most likely harbors a mutation. The presence of MSI in the tumor alone is not sufficient to diagnose LS because 10% to 15% of sporadic colorectal cancers exhibit MSI.
MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with LS; MSH6 mutations in about 7% to 10%; and PMS2 mutations in fewer than 5%. Genetic testing for LS is ideally performed in a stepwise manner: testing for MMR gene mutations is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2 testing.
Management of Polyposis Syndromes
FAP has a 100% penetrance, with polyps developing on average around the time of puberty, and the average colorectal cancer diagnosis before age 40. Endoscopic screening should begin around age 10 to 12 years, and operative intervention (colectomy) remains the definitive treatment. For attenuated FAP, colonoscopic surveillance is recommended to begin at age 20 to 30 years, or 10 years sooner than the first polyp diagnosis in the family (FASCRS, 2015). For MUTYH-associated polyposis, colonoscopic surveillance is recommended to start at age 20 to 30 years.
Colonic surveillance in the hamartomatous polyposis syndromes includes a colonoscopy every 2 to 3 years, starting in the teens.
Management of Nonpolyposis Syndromes
People with LS have lifetime risks for cancer as follows: 52% to 82% for colorectal cancer (mean age at diagnosis, 44-61 years); 25% to 60% for endometrial cancer in women (mean age at diagnosis, 48-62 years); 6% to 13% for gastric cancer (mean age at diagnosis, 56 years); and 4% to 12% for ovarian cancer (mean age at diagnosis, 42.5 years; approximately one third are diagnosed before age 40 years). The risk for other LS-related cancers is lower, although substantially increased over that of the general population. For HNPCC or LS, colonoscopic screening should start at age 20 to 25 years. Prophylactic colectomy is based on aggressive colorectal cancer penetrance in the family. Screening and treatment for the extracolonic malignancies in HNPCC also are established (Burke, 1997).
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.
Coding
Effective in 2015, there are CPT codes for genomic sequencing procedures (or “next generation sequencing” panels). If the panel meets the requirements listed in the code descriptor, the following codes may be used:
81435: Hereditary colon cancer syndromes (e.g., Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2
81436: duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH
81445: Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5-50 genes (e.g., ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed
81450: Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA and RNA analysis when performed, 5-50 genes (e.g., BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mRNA expression levels, if performed
81455: Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA and RNA analysis when performed, 51 or greater genes (e.g., ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed
Prior to 2015 there were no specific codes for molecular pathology testing by panels. During that time and currently if the panel does not meet the criteria in the specific code descriptors, if the specific analyte is not listed in the more specific CPT codes, unlisted code 81479 would be reported. The unlisted code would be reported once to represent all of the unlisted analytes in the panel.
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Policy/ Coverage: |
Effective January 2025, Assessment of Measurable Residual Disease was moved to policy 2024083. Please see policy 2024083 for coverage of measurable residual disease.
Effective January 2025
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this policy or other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
General genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above or addressed in other policies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above or addressed in other policies are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 2023 – December 2024
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this policy or other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of 10-4 (10 to the power of -4) as an alternative test in individuals with acute lymphoblastic leukemia meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (e.g., clonoSEQ) to detect MRD at a threshold of 10-4 (10 to the power of -4) as an alternative test in individuals with chronic lymphocytic leukemia meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (e.g., clonoSEQ) to detect MRD at a threshold of 10-5 (10 to the power of -5) as an alternative test in individuals with multiple myeloma meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with acute lymphoblastic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with acute lymphoblastic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with chronic lymphocytic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in individuals with chronic lymphocytic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-5 (10 to the power of -5) in individuals with multiple myeloma does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (e.g., clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-5 (10 to the power of -5) in individuals with multiple myeloma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
General genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease (MRD) in any situation not described above, including but not limited to the assessment of MRD in individuals with diffuse large B-cell lymphoma or mantle cell lymphoma, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, next-generation sequencing for the assessment of measurable residual disease (MRD) in any situation not described above, including but not limited to the assessment of MRD in individuals with diffuse large B-cell lymphoma or mantle cell lymphoma, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2023
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of this policy or other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of 10-4 (10 to the power of -4) as an alternative test in patients with acute lymphoblastic leukemia meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-4 (10 to the power of -4) as an alternative test in patients with chronic lymphocytic leukemia meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-5 (10 to the power of -5) as an alternative test in patients with multiple myeloma meets member benefit certificate primary coverge criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with acute lymphoblastic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with acute lymphoblastic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with chronic lymphocytic leukemia does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of less than 10-4 (10 to the power of -4) in patients with chronic lymphocytic leukemia is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10-5 (10 to the power of -5) in patients with multiple myeloma does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, next-generation sequencing (eg clonoSEQ) to detect measurable residual disease at a threshold of less than 10-5 (10 to the power of -5) in patients with multiple myeloma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
General genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) for any situation not described above are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease in any situation not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, next-generation sequencing for the assessment of measurable residual disease in any situation not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to January 2021
In general, genetic cancer susceptibility panels are not covered, however, when coverage criteria of other policies are met (see policies 1998051, 2004038, 2014013, 2015004, 2015002, 2013010), limited genetic cancer susceptibility panels, including only the gene variants for which a given member qualifies, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
General genetic cancer susceptibility panels (with or without next generation sequencing) do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to Novermber 2020
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic cancer susceptibility panels (with or without next generation sequencing) do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels (with or without next generation sequencing) are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2018
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic cancer susceptibility panels using next generation sequencing do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels using next generation sequencing are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Next-generation sequencing for the assessment of measurable residual disease does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, Next-generation sequencing for the assessment of measurable residual disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to November 2018
Genetic cancer susceptibility panels using next generation sequencing do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, genetic cancer susceptibility panels using next generation sequencing are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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This evidence review was created in June 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 21, 2024.
Hereditary Cancer Panels
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 (e.g., environmental exposures, personal behaviors) or by the presence or absence of variants in other genes.
Susswein et al reviewed the genetic test results and clinical data from a consecutive series of 10,030 patients referred for evaluation by 1 of 8 hereditary cancer panels (comprising combinations of 29 genes) between August 2013 and October 2014 (Susswein, 2016). Personal and family histories of cancer were obtained, and patients were categorized as having breast, colon, stomach, ovarian, endometrial, or pancreatic cancer; other cancer types were not singled out for analysis. Genetic variants were classified as pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, or benign according to the 2007 guidelines from the American College of Medical Genetics and Genomics (Richards, 2008).
Genes included in the panels were grouped into 3 risk categories based on penetrance data available in 2012, as follows:
Overall, 9.0% (901/10,030) of the patients were found to carry at least 1 pathogenic or likely pathogenic variant, totaling 937 variants. Approximately half of the positive results were in well-established genes (including BRCA1 and BRCA2, Lynch syndrome, and other high-risk genes) and approximately half in genes with moderate or unknown risk. Likely pathogenic variants comprised 10.6% (99/937) of all positive results.
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.
For the breast cancer high-risk panels 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 (BRCA1, BRCA2, CDH1, PTEN, STK11, and TP53). For patients with breast cancer, 9.7% (320/3,315) 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 included TP53, PTEN, and CDH1, 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, BRCA1 and BRCA2 accounted for 50.5% of the 89 variants identified, 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) were within a Lynch gene, most commonly MSH6; CHEK2 was positive in 7%, with an overall frequency of 1.5%; and 6 positive results (10.9%) were identified in BRCA1 and BRCA2.
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]).
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 (NCCN) guideline criteria for TP53 testing, resulting in a frequency of 0.06% (6/9,605) unanticipated positive results. Four patients had a positive CDH1 result, 2 of whom did not meet the International Gastric Cancer Linkage Consortium testing criteria, resulting in a frequency of 0.02% (2/8,708) positive CDH1 results.
Overall, yields among patients with breast, ovarian, and colon/stomach cancers were 9.7%, 13.4%, and 14.8%, 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% (17/3,315), 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 colorectal cancer (CRC) genes. Over 11% of 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 reported on the clinical and molecular characteristics of 2,079 patients who underwent panel testing with Ambry's BreastNext (n=874), OvaNext (n=222), ColoNext (n=557), or CancerNext (n=425) (LaDuca, 2014). 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. 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 reported on 1,085 cases with non-BRCA1 or BRCA2 breast cancer referred to a commercial laboratory that were found to have a pathogenic or likely pathogenic variant (O’Leary, 2017). The cases were divided into 3 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 findings 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. Rates of VUS 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 evaluated 21 genetic predisposition genes for breast cancer in a sample of 38,326 white women with breast cancer who received any one of a variety of genetic test panels (Ambry Genetics) (Couch, 2017). The frequency of pathogenic variants was estimated at 10.2%. After the exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, TP53), 5 additional genes with variants classified as pathogenic by ClinVar were associated with a high or moderately increased risk of breast cancer (Table 1). Notably, of the various panels included in this study, only the BRCA plus 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.
Moderate-to-High Risk Non-BRCA1 and BRCA2, Nonsyndromic Genes Associated With Breast Cancer
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 included over 35,000 women with breast cancer who were assessed with the Myriad 25-gene panel (Buys, 2017). 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 evaluated the frequency of pathogenic variants identified with the 25-gene panel (Myriad Genetics) in 3,088 patients with a personal history of ovarian cancer who were referred for testing (Langer, 2016). 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 NCCN 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), 26.8% in genes with a low-to-moderate increase in cancer risk (ATM, BRIP1, CHEK2, RAD51C, PALB2, NBN), and less than 1% each in 6 other genes. One or more VUS were reported in 1141 (36.9%) of patients.
Kurian et al evaluated the association between gene variants on the Myriad 25-gene panel in 95,561 women and documented risk of breast or ovarian cancer from provider-completed test requisition forms (Kurian, 2017). Pathogenic variants were detected in 6,775 (7%) of the women. Multivariate regression models and case-control analysis estimated that 8 genes were associated with breast cancer with odds ratio (OR) from 2-fold (ATM) to 6-fold (BRCA1). Eleven genes were associated with ovarian cancer, with OR ranging from 2-fold (ATM) to 40-fold (STK11), but statistical significance was achieved for only 3 genes (BRCA1, BRCA2, RAD51C). The clinical significance of the increase in cancer risk for the other genes is uncertain. Out of the 25 genes tested on the panel, there was overlap of 3 genes (ATM, BRCA1, BRCA2) for the association of both breast or ovarian cancer, and not all genes on the panel were associated with risk for either cancer.
Colorectal Cancer
Pearlman et al reported on the prevalence of germline pathogenic variants among patients with CRC in the Ohio Colorectal Cancer Prevention Initiative (Pearlman, 2021). All 3,310 patients enrolled in the study underwent testing for mismatch repair deficiency, and patients meeting at least 1 clinical criterion (mismatch repair deficiency, CRC diagnosis at less than 50 years of age, multiple primary tumors [CRC or endometrial cancer], or first degree relative with CRC or endometrial cancer) underwent subsequent multigene panel testing. The specific multigene panel test used depended on the results of mismatch repair deficiency testing; patients with mismatch repair deficiency not explained by MLH1 hypermethylation (n=224) underwent testing with ColoSeq or BROCA panels, while patients with MLH1 hypermethylated tumors (n=99) and patients without mismatch repair deficiency (n=1,139) underwent testing with a myRisk panel. Panels tested for 25 to 66 cancer genes. Among the 1,462 patients who underwent multigene panel testing, 248 pathogenic or likely pathogenic variants were detected in 234 patients (16% of patients who underwent multigene panel testing, and 7.1% of the entire study population). One hundred forty two pathogenic variants were in mismatch repair deficiency genes, while 101 were in non-mismatch repair deficiency genes. If mismatch repair deficiency testing had been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) of patients with a pathogenic variant in a cancer susceptibility gene or constitutional hypermethylation would have been missed, including 6.3% (9 of 144) of those with Lynch syndrome. One hundred seventy-five patients (5.3% of the entire study population) had pathogenic variants in genes with therapeutic targets. Variants of uncertain significance were found in 422 patients who underwent multigene panel testing (28.9%).
In an industry-sponsored study, Cragun et al reported on the prevalence of clinically significant variants and VUS among patients who underwent ColoNext panel testing (Cragun, 2014). For the period included in the study (March 2012 to 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 NCCN 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 versus a second-tier test (i.e. after syndrome-based testing is negative), remains to be determined.”
Pan-Cancer Panels
Rosenthal et al published an industry-sponsored study evaluating a 25-gene pan-cancer panel (Rosenthal, 2017). The analysis included 252,223 consecutive individuals, most of whom (92.8%) met testing criteria for hereditary breast and ovarian cancer and/or Lynch syndrome. Pathogenic variants (n=17,340) were identified in 17,000 (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.
Idos et al conducted a prospective study that enrolled 2,000 patients who had been referred for genetic testing at 1 of 3 academic medical centers (Idos, 2018). 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. Twelve percent of the patients were found to have a pathogenic variant; 66% of these findings were anticipated by the genetic clinician and 34% 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. 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.
Lumish et al 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 (Lumish, 2017). 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.
Eliade et al evaluated the clinical actionability of a multi-gene panel in a cohort of 583 patients with a family history of breast or ovarian cancer (Eliade, 2017). 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 in 2 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 4 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.
Kurian et al evaluated the information from a next-generation sequencing (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 (Kurian, 2014). 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. Of the women who tested negative for BRCA1 and BRCA2 variants (n=141), 16 had pathogenic variants in other genes (11.4%). 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 6 with variants in CDH1, MLH1, and MUTYH were advised to consider frequent colonoscopy and/or endoscopic gastroduodenoscopy (once every 1 to 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. No clinical outcomes associated with the recommendations were reported.
American Society of Clinical Oncology
In 2015, the American Society of Clinical Oncology (ASCO) issued a policy statement on genetic and genomic testing for cancer susceptibility (Robson, 2015). The update addressed the application of next-generation sequencing (NGS) 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 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.
In 2020, ASCO published a guideline on germline and somatic tumor testing in epithelial ovarian cancer (Konstantinopoulos, 2020). Based on a systematic review of evidence and expert panel input, ASCO recommended that women with epithelial ovarian cancer should be offered germline testing for BRCA1/2 and other specified ovarian susceptibility genes with a multi-gene panel. It was considered more practical to evaluate a minimum of the 10 genes that have been associated with inherited risk of ovarian cancer in a panel in comparison to testing BRCA1 and BRCA2 alone.
In 2024, ASCO published guidance on the selection of germline genetic testing panels in patients with cancer (Tung, 2024). Based on a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing, an ASCO expert panel developed relevant recommendations. They stated that "patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered." They provide specific guidance on strongly recommended genes to test for based on risk and cancer type, along with less strongly recommended genes.
Collaborative Group of the Americas on Inherited Gastrointestinal Cancer
In 2020, the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer published a position statement on multi-gene panel testing for patients with colorectal cancer and/or polyposis (Heald, 2020). Recommendations were based on the evidence, professional society recommendations endorsing testing of a given gene, and opinion of the expert panel. The group noted the variability in genes included in commercially available panels, and recommended that multi-gene panels include a minimum of 11 specific genes associated with defective mismatch repair (Lynch syndrome) and polyposis syndromes. Additional genes to be considered had low to moderately increased risk, had limited data of colorectal cancer risk, or causation for colorectal cancer was not proven.
National Comprehensive Cancer Network
Breast and Ovarian Cancers
National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast, ovarian cancers, and/or pancreatic cancer (v3.2024) include the following on multi-gene testing (NCCN, 2024):
The NCCN defines a "tailored" multi-gene panel test as a "disease-focused multi-gene panel of clinically actionable cancer susceptibility genes, in contrast to large multi-gene panels of uncertain or unknown clinical relevance." The NCCN cautions that multi-gene panels may include moderate-risk genes that have limited data on the degree of cancer risk and no clear guidelines on risk management. As more genes are tested, the likelihood of finding variants of uncertain significance increases. Multi-gene panel testing also increases the likelihood of finding pathogenic/likely pathogenic variants without clear significance.
Colorectal, Endometrial, and Gastric Cancers
The NCCN guidelines on genetic/familial high-risk assessment for colorectal, endometric, and gastric cancers (v1.2024) state that “when more than one gene can explain an inherited cancer syndrome, multi-gene testing is more efficient than single-gene testing, or sequential single syndrome testing" and “there is also a role for multi-gene testing in individuals who have tested negative (indeterminate) for a single syndrome, but whose personal or family history remains strongly suggestive of an inherited susceptibility" (NCCN, 2024). However, the NCCN cautioned about the increased likelihood of finding variants of uncertain significance, which increases with the number of genes included in the panel, and that gene panels can include moderate-risk genes that may not be clinically actionable.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has recommended that primary care providers screen women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool (USPSTF, 2024). 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.
Medicare National Coverage
In January 2020, the Centers for Medicare and Medicaid Services (CMS) determined that NGS is covered for patients with breast or ovarian cancer when the diagnostic test is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory AND the test has approval or clearance by the U.S. Food and Drug Administration (CAG-00450R).
CMS states that local Medicare carriers may determine coverage of NGS for management of the patient for any cancer diagnosis with a clinical indication and risk factor for germline testing of hereditary cancers when performed in a CLIA-certified laboratory.
Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed below.
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