Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN)

POLICY NUMBER

A.2.04.149

DESCRIPTION

It is estimated that approximately 20% of women presenting for assessment for hereditary ovarian cancer risk have a variant in a gene that increases the risk of cancer. BRIP1, RAD51C, RAD51D, NBN, and mismatch repair genes are estimated to contribute to 10% of hereditary ovarian cancer cases. Approximately 60% of the familial relative risk in ovarian cancer is unexplained. Risk for BRIP1, RAD51C, RAD51D, and NBN carriers is increased approximately 3- to 19-fold, 3- to 6-fold, 5- to 12-fold, and 2- to 3.5-fold respectively. Risk estimates may be higher in patients with a family history of ovarian cancer or a family history of a specific gene variant.

Ovarian Cancer and Genetics

In 2024, it is estimated that there will be 20,890 new diagnosed cases of ovarian cancer and that an estimated 12,730 women will die from their disease. Over 95% of ovarian cancers (OC) are derived from epithelial cells. High-grade serous epithelial ovarian carcinoma, fallopian tube carcinoma, and primary peritoneal carcinomas are thus considered a single clinical entity (ie, epithelial ovarian cancer [EOC]) due to their shared pathologic behavior and treatment. Based upon data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program, approximately 1.1% of women in the United States will be diagnosed with OC in their lifetime.

Due to the limited benefit of presymptomatic screening for OC, identifying women at high risk of the disease who may benefit from prophylactic risk-reducing surgery is critically important. Approximately 70% of women are diagnosed with late-stage disease, resulting in a 5-year relative survival rate of 29% compared to 92% for early-stage disease. It is estimated that more than 20% of women diagnosed with OC have a hereditary predisposition to the disease, harboring loss-of-function (LoF) mutations in cancer-related genes. Most of the identified germline mutations in OC occur in the highly penetrant BRCA1 and BRCA2 genes which regulate DNA repair. It is estimated that high penetrance variants in BRCA1 and BRCA2 genes account for ~27% of familial ovarian cancer cases. Mutations in these genes result in homologous recombination deficiency (HRD), which has been targeted with platinum-based chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors. Other mechanisms of HRD lead to a phenotype known as BRCAness, and include germline and somatic mutations in genes related to homologous recombination (HR), epigenetic modifications, and EMSY amplification or overexpression. Homologous recombination-related genes with a documented association with OC risk include BRIP1, RAD51C, and RAD51D, and may represent the most important OC predisposition genes after BRCA1/2. Hereditary OC risk may also be influenced by mismatch repair (MMR) genes and variants in PALB2. BRIP1, RAD51C, and RAD51D, and the mismatch repair genes are estimated to contribute to 10% of hereditary ovarian cancer cases. Approximately 60% of the familial relative risk in ovarian cancer is unexplained. Risk estimates may be higher in patients with a family history of ovarian cancer or a family history of a specific gene variant.

Testing for germline pathogenic variants in BRCA1/BRCA2 and PALB2 is addressed separately in the Germline Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers medical policy.

Mismatch repair genes associated with Lynch syndrome are addressed in the Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes medical policy.

Testing for germline ATM variants is addressed separately in the Germline Genetic Testing for Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1) medical policy.

Penetrance of Pathogenic Variants

Penetrance is the risk conferred by a pathogenic variant or the proportion of individuals with the variant expected to develop cancer. For example, a woman's lifetime risk for developing ovarian cancer is roughly 36% to 63% for BRCA1 carriers and 10% to 27% for BRCA2 carriers. Penetrance can be modified by environmental factors and by family history, which is an important modifier for low and moderate penetrance genes. Moreover, specific pathogenic variants within a gene may confer somewhat different risks.

There is no consensus on how to calculate lifetime risk. Cumulative lifetime risk (CLTR) may be calculated as a multiple of the US Surveillance, Epidemiology, and End Results (SEER) Program estimates of 'ever' developing cancer combined with the average relative risk for the gene variant in question. Other experts may calculate risk of cancer development by a defined age, which is often described as lifetime penetrance. Others describe remaining lifetime risk (LTR) as the CLTR remaining after an individual reaches a particular age. The lack of a consensus for defining LTR may confound guidelines based on this measurement. It is also important to note that the risk threshold separating moderate-penetrance from high-penetrance genes is defined arbitrarily. Average relative risks may not account for individual risk modifications due to genetic and non-genetic factors.

Determining Variant Pathogenicity

Determining the pathogenicity of variants in a more commonly detected cancer susceptibility gene (eg, founder sequence mutations) is generally straightforward because associations are repeatedly observed. For uncommonly identified variants, such as those found in a few individuals or families, defining pathogenicity can be more difficult. For example, predicting the pathogenicity of previously unidentified variants typically requires in silico (computational) analysis predicting protein structure/function, evolutionary conservation, and splice site prediction. The approach to defining pathogenicity is clearly outlined in standards and reporting guidelines. Still, distinctions between a variant of uncertain significance and a pathogenic one from different laboratories may not always be identical.

Genes Associated With a Moderate-to-High Penetrance of Ovarian Cancer

BRIP1 Gene

The BRIP1 (BRCA1 interaction protein C-terminal helicase 1) gene, also known as FANCJ, is located at 17q23.2 and encodes a protein which binds to BRCA1 C-terminal domain (BRCT) repeats in BRCA1 via a nuclear localization signal in its helicase domain to facilitate DNA repair. Biallelic germline mutations result in Fanconi anemia, which is also seen in BRCA2 germline mutations. BRIP1-inactivating truncating and frameshift mutations have been associated with an increased risk of ovarian cancer. Ovarian tumors from heterozygous carriers of the c.1702_1703del mutation showed loss of the wildtype allele, suggesting behavior typical of a classical tumor suppressor gene.

RAD51 Genes

The RAD51 paralogs, RAD51C and RAD51D, are involved in the FA-BRCA1/2 homologous recombination pathway. Biallelic missense mutations in the RAD51C gene are associated with a Fanconi anemia-like phenotype. These mutations are rare and are associated with an increased risk of ovarian cancer as well as a potential increased risk of triple-negative breast cancer.

NBN Gene

The NBN gene encodes the nibrin protein, which is mapped within a critical region for Nijmegen breakage syndrome (NBS) on chromosome 8q21. The encoded protein, also known as p95, is a member of the MRE11/RAD50 double-strand break repair complex and is implicated in cell cycle checkpoint functions and cellular responses to ionizing radiation.

Identifying Women at Risk of an Inherited Susceptibility to Ovarian Cancer

Risk factors for ovarian cancer include older age, early menarche or late menopause, family history of disease, genetic factors, nulliparity, endometriosis, and exposure to asbestos. Risk assessed through family history is dependent on the number and closeness of affected relatives, the age at which cancer developed, and if other cancers occurred (eg, breast). For women without ovarian cancer, the probability of detecting a pathogenic variant can be estimated from a detailed multigenerational pedigree (eg, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), screening tools (eg, BRCAPRO), or by referring to guidelines that define specific family history criteria. For women with ovarian cancer, family history also affects the likelihood of carrying a pathogenic variant.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. BRIP1, RAD51C, RAD51D, and NBN testing are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories offering to test and voluntarily list are available through the National Center for Biotechnology Genetic Testing Registry. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

Customized next-generation sequencing panels provide simultaneous analysis of multiple cancer predisposition genes, and typically include both moderate- and high-penetrance genes.

Myriad Genetic Laboratories offers the myRisk® Hereditary Cancer multi-gene panel test which includes 35 genes. Testing for ovarian cancer risk includes analysis of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, STK11, PALB2, BRIP1, RAD51C, and RAD51D genes.

Ambry Genetics offers the BRCANext-Expanded® panel which includes 23 genes associated with risk of gynecologic cancer, including BRIP1, RAD51C, and RAD51D. Testing for NBN is also included in this panel.

POLICY

Testing for germline BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults may be considered medically necessary when the following criteria are met:

• The individual has a diagnosis of epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; AND

  • The individual has not previously been tested for these gene variants; AND

  • The individual is thought to be the most informative member of a family (proband) to have genetic testing (see Policy Guidelines); AND

  • The individual has closely related (first- and/or second-degree) relatives who are considering genetic testing for these gene variants to inform prophylactic decision-making or who have test results that cannot be fully interpreted without testing an affected relative; OR

• The individual has not been diagnosed with epithelial ovarian cancer; AND

  • The individual has any blood relative with a known pathogenic/likely pathogenic germline BRIP1, RAD51C, or RAD51D variant; OR

  • The individual has a 1st- or 2nd-degree relative diagnosed with ovarian cancer^a.

Testing for germline NBN variants for ovarian cancer risk assessment in adults is considered investigational.

Testing for germline BRIP1, RAD51C, RAD51D, and NBN variants in individuals diagnosed with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer to guide treatment of the diagnosed individual is considered investigational.

Testing for germline BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk in adults who do not meet the criteria above is considered investigational.

^aFor familial assessment, 1st- and 2nd-degree relatives are blood relatives on the same side of the family (maternal or paternal):

• 1st-degree relatives: parents, siblings, and children

• 2nd-degree relatives: grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Recommended Genetic Testing Strategies

Individuals who meet criteria for germline (not somatic) genetic testing as outlined in the policy statements should be tested for variants in BRIP1, RAD51C, and RAD51D. Recommended strategies are listed below.

• In individuals with a known familial germline BRIP1, RAD51C, or RAD51D variant, targeted testing for the specific variant is recommended.

• In individuals with an unknown familial germline BRIP1, RAD51C, or RAD51D variant:

  • To identify clinically significant variants, the National Comprehensive Cancer Network (NCCN) advises testing a relative who has early-onset disease, bilateral disease, or multiple primaries, because that individual has the highest likelihood of obtaining an informative, positive test result. This individual, the first-affected individual in a family who brings a genetic disorder to the attention of the medical community, is commonly referred to as the proband.

  • Testing undiagnosed, at-risk family members when a diagnosed relative is unavailable for testing, is unwilling to undergo testing, or is unwilling to share genetic testing results, should still be considered. However, indeterminate genetic testing results may be poorly understood by family members. Therefore, significant limitations of interpreting test results, including uninformative negative results or non-actionable variants of unknown significance (VUS), should be discussed.

Germline genetic testing for BRCA1, BRCA2, and PALB2 is addressed separately in the Germline Genetic Testing for BRCA1 or BRCA2 for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers medical policy.

This policy applies to testing for ovarian cancer risk assessment, and does not address testing for autosomal recessive conditions associated with BRIP1, RAD51C, or NBN.

Testing for ATM in the context of hereditary breast cancer is addressed separately in the Germline Genetic Testing for Gene Variants Associated With Breast Cancer in Individuals at High Breast Cancer Risk (CHEK2, ATM, and BARD1) medical policy. NCCN recommends that ATM carriers at risk for epithelial ovarian cancer should be managed based on family history alone.

Testing Undiagnosed, At-Risk Individuals

In unaffected (ie, undiagnosed), at-risk family members of potential BRIP1, RAD51C, or RAD51D variant families, most test results will be negative and uninformative. Therefore, it is strongly recommended that an affected (ie, diagnosed) family member be tested first whenever possible to adequately interpret the test. Should a causative variant be found in an affected family member(s), DNA from an unaffected family member can be tested specifically for the same variant of the affected family member without having to sequence the entire gene. Interpreting test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated variant but leads to difficulties in interpreting uninformative negative test results or VUS because the possibility of a causative variant is not ruled out. Non-actionable VUS are highly prevalent with multi-gene testing, which may be avoided with targeted testing for a known familial variant.

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

 Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

1. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

2. appropriate with regard to standards of good medical practice; and

3. not solely for the convenience of the Member, his or her Provider; and

4. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

09/01/2021: New policy added. Approved by Medical Policy Advisory Committee.

05/02/2022: Policy title changed from "Molecular Testing for Variants Associated with Hereditary Ovarian Cancer" to "Molecular Testing for Germline BRIP1, RAD51C, and RAD51D Variants Associated with Ovarian Cancer." Policy description updated. Policy section updated to add medically necessary criteria. Added statement that testing for germline BRIP1, RAD51C, and RAD51D variants in individuals diagnosed with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer to guide treatment of the diagnosed individual is considered investigational. Policy Guidelines updated to add recommended genetic testing strategies and information regarding testing undiagnosed, at-risk individuals.

03/15/2023: Policy title changed from "Molecular Testing for Germline BRIP1, RAD51C, and RAD51D Variants Associated with Ovarian Cancer" to "Molecular Testing for Germline Variants Associated with Ovarian Cancer (BRIP1, RAD51C, RAD51D, NBN)." Policy description updated regarding new data for ovarian cancer and to add information regarding the NBN gene. Policy section updated to add testing for germline NBN variants as investigational. Revised investigational statement to add "for ovarian cancer risk" for clarification. Policy Guidelines updated with minor wording changes, to add links to related policies, and regarding the application of the policy. Code Reference section updated to add ICD-10 diagnosis codes C48.0 - C48.8 and C57.00 - C57.02. Added CPT code 81479 as investigational.

10/09/2023: Policy updated regarding ovarian cancer and genetics. Policy statements unchanged. Policy Guidelines updated regarding the ATM gene.

09/11/2024: Policy description updated regarding new ovarian cancer data. Policy statements unchanged.

09/17/2025: Policy description updated regarding new data for ovarian cancer. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.149

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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