It is estimated that approximately 20% of women presenting for assessment for hereditary ovarian cancer (OC) 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 OC cases. Approximately 60% of the familial relative risk in OC 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 OC or a family history of a specific gene variant.
Germline genetic testing for BRCA1, BRCA2, and PALB2 is addressed separately in evidence review 2.04.02.
Germline genetic testing for ATM is addressed separately in evidence review 2.04.126.
For individuals without diagnosed epithelial ovarian cancer (EOC) and in a family at risk of developing EOC who receive germline genetic testing for genes associated with hereditary ovarian cancer (OC) (ie, BRIP1, RAD51C, and RAD51D), the evidence includes studies of clinical validity and studies of OC risk, including meta-analyses. Relevant outcomes are overall survival (OS), disease-specific survival, and test validity. Evidence supporting clinical validity was obtained from numerous studies reporting relative risk (RR) or odds ratios (OR) and 4 studies provided penetrance estimates. Study designs included family-based case-control and population- or multicenter-based case-control. The number of pathogenic (P)/likely pathogenic (LP) variants identified in association studies ranged from 10 to 36, 11 to 44, and 8 to 13 for BRIP1, RAD51C, and RAD51D, respectively. The RR for OC associated with BRIP1 ranged from 3 to 19, with population-based studied reporting the 2 highest and lowest values. The RR for OC associated with RAD51C ranged from 3 to 6, with a family-based study reporting the highest value. The RR for OC associated with RAD51D ranged from 5 to 12, with family- and population-based studies reporting the highest values. Evidence of preventative interventions in women with BRIP1, RAD51C, and RAD51D variants is indirect, relying on studies of high-risk women and BRCA carriers. These interventions include chemoprevention with oral contraceptives and risk-reducing oophorectomy and risk-reducing salpingo-oophorectomy (RRSO). Given the penetrance of BRIP1, RAD51C, and RAD51D variants, the outcomes following risk-reducing oophorectomy and RRSO examined in women with a family history consistent with hereditary OC (including BRCA1 and BRCA2 carriers) can be applied to women with BRIP1, RAD51C, and RAD51D variants, with the benefit-to-risk balance affected by penetrance. In women at high-risk of hereditary OC who would consider risk-reducing interventions, identifying a BRIP1, RAD51C, or RAD51D variant provides a more precise estimated risk of developing OC compared to family history alone and can offer women a more accurate understanding of benefits and potential harms of any intervention. Additionally, RRSO may provide an opportunity for occult gynecologic cancer detection in high-risk BRCA-negative women. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals without diagnosed EOC and in a family at risk of developing EOC who receive germline genetic testing for NBN gene variants, the evidence includes studies of clinical validity and studies of OC risk, including a meta-analysis. Relevant outcomes are OS, disease-specific survival, and test validity. NBN variants have been associated with a 2- to 3.5-fold increased risk of OC across studies. However, a significantly increased frequency of NBN mutations has not been consistently observed in cases versus controls and penetrance estimates have not been reported. Accordingly, national guidelines have not recommended risk-reducing interventions for NBN carriers at this time due to insufficient data to define risk and recommend managing these individuals based on family history alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals without diagnosed EOC and in a family at risk of developing EOC who are considering prophylactic surgery who receive germline genetic testing of first- and/or second-degree relative(s) with a personal history of EOC for genes associated with hereditary OC (ie, BRIP1, RAD51C, and RAD51D) to guide prophylactic decision-making or interpretation of test results in the undiagnosed, at-risk family member, the evidence on the use of preventative interventions is indirect, relying on studies of at-risk women and BRCA carriers. Relevant outcomes are OS, disease-specific survival, and test validity. Evidence of preventative interventions in women with BRIP1, RAD51C, and RAD51D variants is indirect, relying on studies of high-risk women and BRCA carriers. Preventative interventions include chemoprevention with oral contraceptives and risk-reducing oophorectomy and RRSO. Given the penetrance of BRIP1, RAD51C, and RAD51D variants, the outcomes following risk-reducing oophorectomy and RRSO examined in women with a family history consistent with hereditary OC (including BRCA1 and BRCA2 carriers) can be applied to women with BRIP1, RAD51C, and RAD51D variants, with the benefit-to-risk balance affected by penetrance. In women at risk of hereditary OC who are considering prophylactic surgery, genetic testing of first- and/or second-degree relative(s) with a personal history of EOC to identify a familial BRIP1, RAD51C, or RAD51D germline variant provides a more precise estimated risk of developing OC compared to family history alone, and reduces the incidence of uninformative negative test results or non-actionable variants of unknown significance (VUS). Identification of and targeted testing for a known familial variant can offer women a more accurate understanding of benefits and potential harms of prophylactic surgery, and is a testing strategy supported by national guidelines. Testing a relative with early-onset disease, bilateral disease, or multiple primaries is recommended, as that individual has the highest likelihood of obtaining an informative, positive test result. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals without diagnosed EOC and in a family at risk of developing EOC who are considering prophylactic surgery who receive germline genetic testing of first- and/or second-degree relative(s) with a personal history of EOC for NBN gene variants to guide prophylactic decision-making or interpretation of test results in the undiagnosed, at-risk family member, direct evidence is lacking. Relevant outcomes are OS, disease-specific survival, and test validity. National guidelines have not recommended prophylactic surgery due to insufficient data to establish absolute risk estimates. Given that the clinical validity of NBN germline variant testing has not been established, a chain of evidence cannot be constructed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with diagnosed OC who receive germline genetic testing for BRIP1, RAD51C, RAD51D, and NBN gene variants to guide treatment decisions in the individual with diagnosed EOC, the evidence includes studies of variant prevalence and studies of OC risk. Relevant outcomes are OS, disease-specific survival, and test validity. Direct evidence for the clinical utility of genetic testing for BRIP1, RAD51C, RAD51D, and NBN variants in individuals with OC was not identified. Due to the standard surgical management of OC patients, the clinical utility of BRIP1, RAD51C, RAD51D, and NBN variant testing to inform therapy was reviewed. In studies evaluating homologous recombination deficiency (HRD) assays in BRCA wild-type patients, an overlapping therapeutic benefit was found between deficient/high loss-of-heterozygosity and proficient/low loss-of-heterozygosity tumors and results were not stratified by non-BRCA HRD genes. The use of BRIP1, RAD51C, RAD51D, and NBN variant status to guide maintenance and recurrence therapy continues to be elucidated in the clinical trial setting. In contrast to undiagnosed women at high familial risk of OC, women diagnosed with OC who undergo testing for BRIP1, RAD51C, RAD51D, and NBN variants do not yield clinically actionable results. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
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 first- or second-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.
a For familial assessment, first- and second-degree relatives are blood relatives on the same side of the family (maternal or paternal):
First-degree relatives: parents, siblings, and children.
Second-degree relatives: grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.
| CPT | 0102U | Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with mRNA analytics to resolve variants of unknown significance when indicated (17 genes [sequencing and deletion/duplication]) |
| 0103U | Hereditary ovarian cancer (eg, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis panel utilizing a combination of NGS, Sanger, MLPA, and array CGH, with mRNA analytics to resolve variants of unknown significance when indicated (24 genes [sequencing and deletion/duplication], EPCAM [deletion/duplication only]) | |
| 0131U | Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (13 genes) (List separately in addition to code for primary procedure) | |
| 0132U | Hereditary ovarian cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), targeted mRNA sequence analysis panel (17 genes) (List separately in addition to code for primary procedure) | |
| 0134U | Hereditary pan cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (18 genes) (List separately in addition to code for primary procedure) | |
| 0135U | Hereditary gynecological cancer (eg, hereditary breast and ovarian cancer, hereditary endometrial cancer, hereditary colorectal cancer), targeted mRNA sequence analysis panel (12 genes) (List separately in addition to code for primary procedure) | |
| 81432 | Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 | |
| 81433 | Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11 |
| ICD-10-CM | C48.0-C48.8 | Malignant neoplasm of the peritoneum code range |
| C56.1-C56.9 | Malignant neoplasm of the ovary code range | |
| C57.00-C57.02 | Malignant neoplasm of the fallopian tube code range | |
| Z80.41 | Family history of ovarian cancer |
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 (Himes et al [2019]; PMID 31199558). 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 evidence review 2.04.02.
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. Germline testing for Fanconi Anemia addressed separately in evidence review 2.04.128.
Testing for ATM in the context of hereditary breast cancer is addressed separately in evidence review 2.04.126. NCCN recommends that ATM carriers at risk for epithelial ovarian cancer should be managed based on family history alone.
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 (Himes et al [2019]; PMID 31199558). Non-actionable VUS are highly prevalent with multi-gene testing, which may be avoided with targeted testing for a known familial variant (Tung et al [2016]; PMID: 27296296).
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 PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.
| Previous | Updated | Definition |
| Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
| Variant | Change in the DNA sequence | |
| Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
| Variant Classification | Definition |
| Pathogenic | Disease-causing change in the DNA sequence |
| Likely pathogenic | Likely disease-causing change in the DNA sequence |
| Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
| Likely benign | Likely benign change in the DNA sequence |
| Benign | Benign change in the DNA sequence |
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Genetic counseling 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.
In 2024, it is estimated that there will be 19,680 new diagnosed cases of ovarian cancer (OC) and that an estimated 12,740 women will die from their disease.1, Over 95% of 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 OC [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.2,
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.3,4, 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 OC cases.5, 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.3,4, Other mechanisms of HRD lead to a phenotype known as BRCAness, and include germline and somatic mutations in genes related to homologous recombination, 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 genes and variants in PALB2. BRIP1, RAD51C, and RAD51D, and the mismatch repair genes are estimated to contribute to 10% of hereditary OC cases.5, Approximately 60% of the familial relative risk in OC is unexplained. Risk estimates may be higher in patients with a family history of OC or a family history of a specific gene variant.
Testing for germline pathogenic variants in BRCA1/BRCA2 and PALB2 is addressed separately in evidence review 2.04.02.
Mismatch repair genes associated with Lynch syndrome are addressed in evidence review 2.04.08.
Testing for germline ATM variants is addressed separately in evidence review 2.04.126.
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 OC is roughly 36% to 63% for BRCA1 carriers and 10% to 27% for BRCA2 carriers.6, 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.7, Cumulative lifetime risk (CLTR) may be calculated as a multiple of the US 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 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.8, The approach to defining pathogenicity is clearly outlined in standards and reporting guidelines. Still, distinctions between a VUS and a pathogenic one from different laboratories may not always be identical.9,
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 BRCT repeats in BRCA1via a nuclear localization signal in its helicase domain to facilitate DNA repair.10, 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 OC. Ovarian tumors from heterozygous carriers of the c.1702_1703del mutation showed loss of the wild-type allele, suggesting behavior typical of a classical tumor suppressor gene.11,
The RAD51paralogs, RAD51C and RAD51D, are involved in the FA-BRCA1/2 homologous recombination pathway.12,13, Biallelic missense mutations in the RAD51C gene are associated with a Fanconi anemia-like phenotype.14, These mutations are rare and are associated with an increased risk of OC as well as a potential increased risk of triple-negative breast cancer.15,
The NBNgene encodes the nibrin protein, which is mapped within a critical region for Nijmegen breakage syndrome (NBS) on chromosome 8q21.16, 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.
Risk factors for OC 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 a women without OC, 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),17, screening tools (eg, BRCAPRO), or by referring to guidelines that define specific family history criteria (see Supplemental Information section on Practice Guidelines and Position Statements). For women with OC, family history also affects the likelihood of carrying a pathogenic variant.17,
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 OC 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.
