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Genetic Cancer Susceptibility Panels Using Next -Generation Sequencing

Number 12.04.93

Effective Date June 17, 2015

Revision Date(s) 06/09/15; 01/13/15; 07/14/14; 01/13/14

Replaces 2.04.93

Policy

Genetic cancer susceptibility panels using next -generation sequencing, including but not limited to GeneDX™, ColoNext™, ColonSentry™ and myRISK™) are considered investigational.

Related Policies

12.04.504

Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (BRCA1/BRCA2)

12.04.506

Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

Policy Guidelines

Although genetic cancer susceptibility panels using next -generation sequencing are considered investigational, there may be individual components of the panel that are medically necessary.

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:

Coding

CPT

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

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.

Description

Numerous genetic mutations are associated with certain types of hereditary cancer. Genetic testing using next-generation sequencing (NGS) technology allows for the analysis of multiple genes at one time (panel testing), and these panels are commercially available. The utility of these genetic panels will be reviewed, in comparison with testing for individual mutations.

Background

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

Several companies, including Ambry Genetics and GeneDx, offer genetic testing panels that use NGS methods for hereditary cancers. NGS refers to 1 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 mutations that are of unclear clinical significance or which would not lead to changes in patient management. Currently available panels do not include all genes associated with hereditary cancer syndromes. In addition, these panels do not test for variants (i.e., single nucleotide polymorphisms [SNPs]), which may be associated with a low, but increased cancer risk.

NGS Cancer Panels

A list of the genes that are included in these panels is given in Tables 1 and 2, followed by a brief description of each gene.

Table 1. Ambry Genetics Hereditary Cancer Panel Tests

Gene Tested

BRCAplus

GYNplus

BreastNext

OvaNext

ColoNext

PancNext

PGLNext

RenalNext

CancerNext

BRCA1

X

X

X

X

 

X

   

X

BRCA2

X

X

X

X

 

X

   

X

ATM

   

X

X

 

X

   

X

BARD1

   

X

X

       

X

BRIP1

   

X

X

       

X

MRE11A

   

X

X

       

X

NBN

   

X

X

       

X

RAD50

   

X

X

       

X

RAD51C

   

X

X

       

X

PALB2

   

X

X

 

X

   

X

STK11

X

 

X

X

X

X

   

X

CHEK2

   

X

X

X

     

X

PTEN

X

X

X

X

X

   

X

X

TP53

X

X

X

X

X

X

 

X

X

CDH1

X

 

X

X

X

     

X

MUTYH

   

X

X

X

     

X

EPCAM MLH1

 

X

 

X

X

X

 

X

X

MSH2

 

X

 

X

X

X

 

X

X

MSH6

 

X

 

X

X

X

 

X

X

EPCAM

 

X

 

X

X

X

 

X

X

PMS2

 

X

 

X

X

X

 

X

X

APC

       

X

X

   

X

BMPR1A

       

X

     

X

SMAD4

       

X

     

X

NF1

   

X

X

   

X

 

X

RAD51D

   

X

X

       

X

CDK4

               

X

CDKN2A

         

X

   

X

RET

           

X

   

SDHA

           

X

X

 

SDHAF2

           

X

   

SDHB

           

X

X

 

SDHC

           

X

X

 

SDHD

           

X

X

 

TMEM127

           

X

   

VHL

           

X

X

 

FH

             

X

 

FLCN

             

X

 

MET

             

X

 

MITF

             

X

 

TSC1

             

X

 

TSC2

             

X

 

GeneDx offers a number of comprehensive cancer panels that use NGS, summarized in Table 2.

Table 2. GeneDx Hereditary Cancer Panel Tests

Gene Tested

Breast/Ovarian Cancer Panel

Breast Cancer High-Risk Panel

Endometrial Cancer Panel

Lynch/ Colorectal Cancer High-Risk Panel

Colorectal Cancer Panel

Pancreatic Cancer Panel

Comprehensive Cancer Panel

BRCA1

X

X

X

   

X

X

BRCA2

X

X

X

   

X

X

ATM

X

     

X

X

X

BARD1

X

         

X

BRIP1

X

         

X

MRE11A

             

NBN

X

           

RAD50

             

RAD51C

X

         

X

PALB2

X

 

X

   

X

X

STK11

X

X

   

X

X

X

CHEK2

X

 

X

 

X

 

X

PTEN

X

X

X

 

X

 

X

TP53

X

X

X

 

X

X

X

CDH1

X

X

   

X

 

X

MUTYH

   

X

X

X

 

X

MLH1

X

 

X

X

X

X

X

MSH2

X

 

X

X

X

X

X

MSH6

X

 

X

X

X

X

X

EPCAM

X

 

X

X

X

X

X

PMS2

X

 

X

X

X

X

X

APC

     

X

X

X

 

BMPR1A

       

X

 

X

SMAD4

       

X

 

X

RAD51D

X

         

X

CDK4

         

X

X

CDKN2A

         

X

X

VHL

         

X

X

XRCC2

X

     

X

X

X

FANCC

           

X

AXIN2

       

X

 

X

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, AXIN2). The University of Washington offers the BROCA Cancer Risk Panel, which is a NGS 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. (1) 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 (CS), Li-Fraumeni syndrome (LFS), Peutz-Jeghers syndrome (PJS), 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. (2)

Myriad Genetics (Salt Lake City, UT) offers the myRISK™ NGS 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.

Genes Included in NGS Panels

The following is a summary of the function and disease association of major genes included in the NGS panels. This is not meant to be a comprehensive list of all genes included in all panels.

BRCA1 and BRCA2

BRCA1 and BRCA2 germline mutations 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 mutations are also associated with increased risk of other cancers, including prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer.

APC

APC germline mutations 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

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 4 years, telangiectasias of the conjunctivae, oculomotor apraxia, immune defects, and cancer predisposition, particularly leukemia and lymphoma.

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

BARD1, BRIP1, MRE11A, NBN, RAD50, and RAD51C are genes in the Fanconi anemia-BRCA pathway. Mutations in these genes are estimated to confer up to a 4-fold increase in the risk for breast cancer.

BMPR1A and SMAD4

BMPR1A and SMAD4 are genes mutated in 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

CHEK2 gene mutations 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

CDH1 germline mutations have been associated with lobular breast cancer in women and with hereditary diffuse gastric cancer. The estimated cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years is 67% for men and 83% for women. CDH1 mutations are associated with a lifetime risk of 39% to 52% of lobular breast cancer.

EPCAM, MLH1, MSH2, MSH6, and PMS2

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%-80% lifetime risk), uterine/endometrial cancer (20% to 60% lifetime risk), gastric cancer (11%-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

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 mutations in the APC gene, have MUTYH mutations.

PALB2

PALB2 germline mutations have been associated with an increased risk of pancreatic and breast cancer. Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern.

PTEN

PTEN mutations have been associated with PTEN hamartoma tumor syndrome, which includes 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

STK11 germline mutations have been associated with 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

TP53 has been associated with LFS. People with TP53 mutations 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

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

RAD51D

RAD51D germline mutations have been associated with familial breast and ovarian cancer.

CDK4

CDK4 (cyclin-dependent kinase-4) is a protein-serine kinase involved in cell cycle regulation. Mutations in this gene have been associated with a variety of cancers, particularly cutaneous melanoma.

CDKN2A

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. Mutations 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

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

SDHA, SDHB, SDHC, SDHD, and SDHAF2

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

TMEM127

TMEM127 (transmembrane protein 127) germline mutations have associated with risk of pheochromocytomas.

VHL

VHL germline mutations are associated with the autosomal dominant familial cancer syndrome Von Hippel-Lindau syndrome, which is associated with a variety of malignant and benign tumors, including central nervous system tumors, renal cancers, pheochromocytomas, and pancreatic neuroendocrine tumors.

FH

FH (fumarate hydratase) mutations have been associated with renal cell and uterine cancers.

FLCN

FLCN (folliculin) acts as a tumor suppressor gene; mutations in this gene are associated with the autosomal dominant syndrome Birt-Hogg-Dube syndrome, which is characterized by hair follicle hamartomas, kidney tumors, and colorectal cancer.

MET

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

MITF

MITF (microphthalmia-associated transcription factor) is a transcription factor involved in melanocyte differentiation. MITF mutations 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

TSC1 (tuberous sclerosis 1) and TSC2 (tuberous sclerosis 2) encode the proteins hamartin and tuberin, which are involved in cell growth, differentiation, and proliferation. Mutations 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

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

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

AXIN2

AXIN2 mutations have been associated with familial adenomatous polyposis syndrome, although the phenotypes associated with AXIN2 mutations 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 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. (3)

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.

Li-Fraumeni Syndrome

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:

  • A proband with a sarcoma diagnosed before age 45 years and
  • A first-degree relative with any cancer before age 45 years and
  • A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age

The 2009 Chompret criteria for LFS / TP53 testing are as follows:

  • A proband who has:
  • A tumor belonging to the LFS tumor spectrum (soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or lung bronchoalveolar cancer) before age 46 years and
  • At least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; or
  • A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; or
  • A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history

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.

Cowden Syndrome

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 (5) 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. (6) 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. (7) 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 (8) 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. (9) 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. (10)

Regulatory Status

Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing. Ambry Genetics is CLIA licensed.

Scope

Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

N/A

Rationale

This policy was created in April 2013 with a review of the literature, and has been updated periodically with literature reviews, most recently through April 15, 2015.

Analytic Validity

Analytic validity is the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent. According to Ambry Genetics, the analytical sensitivity for the 22 genes analyzed on their cancer susceptibility panels by next -generation sequencing (NGS) is 96% to 99%. According to the GeneDx website, their comprehensive cancer susceptibility panel has greater than 99% sensitivity in detecting mutations identifiable by sequencing or array comparative genomic hybridization. (11) This analytic sensitivity approaches that of direct sequencing of individual genes.

To determine whether NGS would enable accurate identification of inherited mutations for breast and ovarian cancer, Walsh et al. developed a genomic assay to capture, sequence, and detect all mutations in 21 genes, (which included 19 of the genes on the BreastNext and OvaNext panels). (12) Constitutional genomic DNA from persons with known inherited mutations, was hybridized to custom oligonucleotides and then sequenced. The analysis was carried out blindly as to the mutation in each sample. All single nucleotide substitutions, small insertions and deletions, and large duplications and deletions were detected. There were no false positive results.

Chong et al. report the design and validation of BRCAplus, a panel that detects mutations in the 6 high-risk breast cancer susceptibility genes BRCA1, BRCA2, CDH1, PTEN, TP53, and STK11 using NGS and array comparative genomic hybridization (aCGH). (13) NGS analysis was confirmed by Sanger sequencing and aCGH analysis (for duplications and deletions) was confirmed by Multiplex Ligation-Dependent Probe Amplification analysis. The analysis was conducted on 250 previously characterized, archived genomic DNA samples, which harbored a total of 3,025 previously defined germline variants in the 6 targeted genes. The BRCAplus test correctly identified all variants, resulting in 100% sensitivity. There were a total of 30 false positives from 5,788,250 base pairs interrogated, resulting in an analytic specificity for NGS of 99.99%

Clinical Validity

Clinical validity is the diagnostic performance of the test—sensitivity, specificity, positive and negative predictive values.

The published literature provides no guidance for the assessment of the clinical validity of panel testing for cancer susceptibility with NGS, and the usual approach to establishing the clinical validity for genetic testing is difficult to apply to panel testing.

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

For genetic susceptibility to cancer, clinical validity can be considered on 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 mutation, but also by other modifying factors that can affect the penetrance of the mutation (e.g., environmental exposures, personal behaviors) or by the presence or absence of mutations in other genes.

In 2014, LaDuca et al. reported the clinical and molecular characteristics of 2079 patients who underwent panel testing with BreastNext, OvaNext, ColoNext or CancerNext (Ambry Genetics). (14) The panels did not include BRCA1/2. The standards for ordering the panels were clinician judgement or clinic-specific thresholds. Most patients (94%) 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.

In 2014, Tung et al. assessed the frequency of pathogenic mutations among patients with breast cancer who were referred for BRCA1/2 testing, using a panel of 25 genes associated with inherited cancer predisposition (Myriad Genetics). (15) The study included 2 cohorts: 1781patients referred for commercial testing for BRCA1/2 testing 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 BRCA1/2 (cohort 2). Mutations were identified in 16 genes, with the most frequent being BRCA1/2, CHEK2, ATM, and PALB2. In cohort 1, a total of 241 (13.5%) individuals were found to have a mutation in at least one of the genes tested, 162 (67%) in BRCA1/2 and 76 (32%) in at least one of the other 23 genes. Three (1%) individuals had a mutation in both BRCA2 and another gene (ATM, CHEK2, or NBN.) When BRCA1/2 mutation carriers were excluded from cohort 1, a mutation was detected with a frequency of 4.7%. In cohort 2, the frequency of mutations in breast-/ovarian-associated genes (other than BRCA1/2) was 2.9%; 0.8% had an incidental mutation. In both cohorts, CHEK2 mutations were the most common non-BRCA1/2 mutations identified, in approximately 33%.

Clinical Utility

Clinical utility is how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.

Related policy General Approach to Evaluating the Utility of Genetic Panels (See Related Policies) outlines criteria that can be used to evaluate the clinical utility of cancer panels. 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?

Identifying a person with a genetic mutation that confers a high risk of developing cancer could lead to changes in clinical management and improved health outcomes. There are well-defined clinical guidelines on the management of patients who are identified as having a high-risk hereditary cancer syndrome. Changes in clinical management could include modifications in cancer surveillance, specific risk-reducing measures (e.g., prophylactic surgery), and treatment guidance (e.g., avoidance of certain exposures). In addition, other at-risk family members could be identified.

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

A limited body of literature exists on the potential clinical utility of available NGS cancer panels. In 2014, in an industry-sponsored study, Cragun et al. reported the prevalence of clinically significant mutations and variants of uncertain significance (VUSs) among patients who underwent ColoNext panel testing. (16) 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 mutation; 2) variant, likely pathogenic; 3) variant, unknown significance; 4) variant, likely benign; and 5) benign. Data was analyzed for 586 patients whose ColoNext testing results and associated clinical data were maintained in a database by Ambry Genetics. Sixty-one patients (10.4%) had genetic alterations consistent with pathogenic mutations or likely pathogenic variants; after 8 patients with only CHEK2 or one MUTYH mutation were removed, 42 patients (7.2%) were considered to have actionable mutations. One hundred eighteen patients (20.1%) had at least 1 variant of uncertain significance, including 14 patients who had at least 1 variant of uncertain significance in addition to a pathologic mutation. Of the 42 patients with a pathologic mutation, most (30 patients [71%]) clearly met National Comprehensive Cancer Network guidelines for syndrome-based testing, screening, or diagnosis, based on the available clinical and family history. The authors note that, “The reality remains that syndrome based testing would have been sufficient to identify the majority of patients with deleterious mutations. Consequently, the optimal and most cost-effective use of panel-based testing as a first-tier test vs. a second tier test (i.e. after syndrome-based testing is negative), remains to be determined.”

Mauer et al. reported a single academic center’s genetics program’s experience with NGS panels for cancer susceptibility.(17) The authors conducted a retrospective review of the outcomes and clinical indications for the ordering of Ambry’s NGS panels (BreastNext, OvaNext, ColoNext, CancerNext) for patients seen for cancer genetics counseling from April 2012 to January 2013. Of 1521 new patients seen for cancer genetics counseling, 1233 (81.1%) had genetic testing. Sixty of these patients (4.9% of total) had a NGS panel ordered, 54 of which were ordered as a second-tier test after single-gene testing was performed. Ten tests were cancelled due to out-of-pocket costs or previously identified mutations. Of the 50 tests obtained, 5 were found to have a deleterious result (10%; compared with 131 [10.6%] of the 1233 single-gene tests ordered at the same center during the study time frame). The authors report that of the 50 completed tests, 30 (60%) did not affect management decisions, 15 (30%) introduced uncertainty regarding the patients’ cancer risks, and 5 (10%) directly influenced management decisions.

In 2014, Kurian et al. evaluated the information from a NGS panel of 42 cancer associated genes in women who had been previously referred for clinical BRCA1/2 testing after clinical evaluation of hereditary breast and ovarian cancer from 2002 to 2012. (18) 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 caner 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 BRCA1/2 mutations. Testing with the panel confirmed 57 of 59 of the pathogenic BRCA1/2 mutations; of the 2 others, 1 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 BRCA1/2 mutations (n=141), 16 had pathogenic mutations 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 5 were novel. 80% of the women with pathogenic mutations in the non BRCA1/2 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 mutations in ATM, BLM, CDH1, NBN, and SLX4 were advised to consider annual breast magnetic resonance imagings because of an estimated doubling of breast cancer risk, and 6 with mutations 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 a MLH1 mutation consistent with LS underwent risk-reducing salpingo-oophorectomy and early colonoscopy which identified a tubular adenoma that was excised (she had previously undergone hysterectomy for endometrial carcinoma).

In summary, 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-intermediate penetrance are not standardized, and the clinical utility of genetic testing for these mutations is uncertain and could potentially lead to harm. In addition, high rates of VUSs have been reported with the use of these panels.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

     

NCT01850654

Ohio Colorectal Cancer Prevention Initiative: Universal Screening for Lynch Syndrome

4000

Sep 2017

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Summary of Evidence

The use of next -generation sequencing (NGS) has made it possible to simultaneously test for multiple mutations. Commercially available Cancer susceptibility mutation panels address multiple specific types of cancer that may have a hereditary component, including breast, ovarian, endometrial, pancreatic, and renal cancers, and paragangliomas. Comprehensive panels are also available that include mutations for a wide variety of cancers. The mutations included in these panels are associated with varying levels of risk of developing cancer, and only some of the mutations are associated with well-defined cancer syndromes which have established clinical management guidelines.

Management guidelines for syndromes with high penetrance in appropriate patient populations 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 -intermediate penetrance are not standardized, and the clinical utility of genetic testing for these mutations is uncertain and could potentially lead to harm. In addition, high rates of variants of uncertain significance (VUSs) have been reported with the use of these panels.

Therefore, the use of genetic cancer susceptibility panels using NGS for breast, ovarian, colon and multiple cancer types is considered investigational.

Practice Guidelines and Position Statements

In a 2010 policy statement update on genetic and genomic testing for cancer susceptibility, the American Society of Clinical Oncology (ASCO) stated that testing for high-penetrance mutations in appropriate populations has clinical utility in that they inform clinical decision making and facilitate the prevention or amelioration of adverse health outcomes but that genetic testing for intermediate-penetrance mutations are of uncertain clinical utility because the cancer risk associated with the mutation is generally too small to form an appropriate basis for clinical decision making. (19) ASCO recommends that genetic tests with uncertain clinical utility (low-to-moderate penetrance mutations) be administered in the context of clinical trials.

National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer state that, regarding multigene testing (20):

  • 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 1 gene can explain an inherited cancer syndrome, then multigene testing may be more efficient and/or cost effective.
  • There is also a role for multigene 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.
  • 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.
  • Multigene 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 multigene 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 VUSs when testing for mutations 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 posttest counseling.

The most recent NCCN guidelines on genetic/familial high risk assessment for colorectal cancer (v2.2014) does not address NGS gene panels. (21)

U.S. Preventive Services Task Force Recommendations

This recommendation is made for women who have family members with breast, ovarian, tubal, or peritoneal cancer. BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. The U.S. Preventive Services Task Force recommends that primary care providers screen women who have family members with breast, ovarian, tubal, or peritoneal cancer with 1 of several screening tools designed to identify a family history that may be associated an increased risk for potentially harmful mutations in breast cancer and susceptibility genes (BRCA1 or BRCA2). Women with a positive screening results should receive genetic counseling and, if indicated after counseling, BRCA testing (grade B recommendation, 2013). The use of genetic cancer susceptibility panels is not specifically mentioned.

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References

  1. Washington Uo. BROCA -- Cancer Risk Panel. http://web.labmed.washington.edu/tests/genetics/BROCA#BROCA_Gene_List. Accessed May, 2015.
  2. Washington Uo. ColoSeq -- Lynch and Polyposis Syndrome Panel. Available online at: http://tests.labmed.washington.edu/COLOSEQ. Last accessed May, 2015.
  3. Shannon KM, Chittenden A. Genetic testing by cancer site: breast. Cancer J. Jul-Aug 2012; 18(4):310-319. PMID 22846731
  4. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. Mar 10 2009; 27(8):1250-1256. PMID 19204208
  5. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. May 2004; 41(5):323-326. PMID 15121767
  6. 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
  7. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am. Oct 2009; 18(4):687-703. PMID 19793575
  8. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. Jun 1999; 116(6):1453-1456. PMID 10348829
  9. Available online at: http://www.fascrs.org/physicians/education/core_subjects/2012/hereditary_colon_cancer_syndromes/. Last accessed May, 2015.
  10. Burke W, Petersen G, Lynch P, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA. Mar 19 1997; 277(11):915-919. PMID 9062331
  11. GeneDx. Test Information Sheet -- OncoGene Dx: Comprehensive Cancer Panel. 2014. Available online at: http://www.genedx.com/wp-content/uploads/2013/09/info_sheet_Comprehensive_cancer_panel.pdf. Last accessed May, 2015.
  12. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. Jul 13 2010; 107(28):12629-12633. PMID 20616022
  13. Chong HK, Wang T, Lu HM, et al. The validation and clinical implementation of BRCAplus: a comprehensive high-risk breast cancer diagnostic assay. PLoS One. 2014;9(5):e97408. PMID 24830819
  14. 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
  15. 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
  16. 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. Feb 9 2014. PMID 24506336
  17. Mauer CB, Pirzadeh-Miller SM, Robinson LD, et al. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med. Oct 10 2013. PMID 24113346
  18. 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
  19. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. Feb 10 2010; 28(5):893-901. PMID 20065170
  20. National Comprehensive Cancer Network (NCCN). Genetic/Familial High Risk Assessment: Breast and Ovarian -- Version 1.2015. 2015; Available online at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Last accessed May, 2015.
  21. National Comprehensive Cancer Network (NCCN). Genetic/Familial High Risk Assessment: Colorectal -- Version 2:2014. 2014; Available online at: http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Last accessed May, 2015.
  22. Blue Cross and Blue Shield Association (BCBSA). Medical Policy Reference Manual, Genetic Cancer Susceptibility Panels Using Next Generation Sequencing. Policy 2.04.93, 2015.

Coding

Codes

Number

Description

CPT

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

 

81455

Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA and RNA analysis when performed, 51 or greater genes (eg, 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

 

81479

Unlisted molecular pathology procedure

Type of Service

Genetic Testing

 

Place of Service

Laboratory/ Physician’s Office

 

Appendix

N/A

History

Date

Reason

11/11/13

New Policy. Add to Genetic Testing section; renumbered (BCBSA policy number is 2.04.93). Policy created with literature review through March 30, 2013. Policy statement that cancer susceptibility testing using next generation sequencing panel testing for inherited breast, ovary, colon and various types of cancer is investigational.

01/13/14

Replace policy. Two additional types of next generation sequencing panels – BROCA and ColoSeq – added to Description section.

03/18/14

Update Related Policies. Add 12.04.92.

05/23/14

Update Related Policies. Add 2.04.115.

07/31/14

Annual Review. Policy updated with literature review through April 7, 2014; references 1, 2, 11, 13, 14, 18 added. Policy statement unchanged.

01/28/15

Interim Update. Myriad Genetics myRISK panel added to list of commercially available next generation sequencing panels and updated NCCN hereditary breast and ovarian cancer screening guidelines which address panel testing. Reference added. Policy statement unchanged.

03/19/15

Update Related Policies. Add 12.04.126.

06/17/15

Annual Review. Policy updated with literature review through April 15, 2015; references 13-15 and 18 added. Policy statement unchanged. Policies 12.04.63, 12.04.88, 12.04.92, 12.04.115, and 12.04.126 removed from Related Policies section. CPT code 81455 added to policy.


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