Coverage Policy Manual
Policy #: 2022018
Category: Laboratory
Initiated: April 2022
Last Review: April 2024
  Genetic Test: Molecular Testing for Germline BRIP1, RAD51C, and RAD51D Variants Associated with Ovarian Cancer
Description:
In 2022, it is estimated that there will be 19,880 new diagnosed cases of ovarian cancer (OC) and that an estimated 12,810 women will die from their disease (ACS, 2022). 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 (i.e., 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 1.2% of women in the United States will be diagnosed with OC in their lifetime (SEER, 2020).
 
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 (Suszynska, 2019; Suszynska, 2020). 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 greater 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 cancers (Jervis, 2015). Mutations in these genes results in homologous recombination deficiency (HRD), which has been targeted with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors (Suszynska, 2019; Suszynska, 2020). 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. HR-related genes with a documented association with OC risk include BRIP1, AD51C, 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 (Jervis, 2015). 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.
 
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 36-63% for BRCA1 carriers and 10-27% for BRCA2 carriers (Domchek, 2010). 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 (Tung, 2016). 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 (e.g., 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 (Richards, 2015). 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 (Kurian, 2016).
 
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 BRCT repeats in BRCA1 via a nuclear localization signal in its helicase domain to facilitate DNA repair (OMIM, 2016). Biallelic germline mutations result in Fanconi anemia (FA), 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 (OMIM, 2019).
 
RAD51C and RAD51D Genes
The RAD51 paralogs, RAD51C and RAD51D, are involved in the FA-BRCA1/2 homologous recombination pathway (OMIM, 2019). Biallelic missense mutations in the RAD51C gene are associated with a Fanconi anemia-like phenotype (Apostolou, 2013). 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 (NCCN, 2019).
 
NBN Gene
The NBN gene encodes the nibrin protein, which is mapped within a critical region for Nijmegen breakage syndrome (NBS) on chromosome 8q21 (OMIM, 2016). 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 (e.g., breast). For a women without ovarian cancer, the probability of detecting a pathogenic variant can be estimated from a detailed multigenerational pedigree (e.g., Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), screening tools (e.g., BRCAPRO), or by referring to guidelines that define specific family history criteria (see Supplemental Information section on Practice Guidelines and Position Statements) (Antoniou, 2004). For women with ovarian cancer, family history also affects the likelihood of carrying a pathogenic variant (Antoniou, 2004).  
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. 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.
 
For BRCA1, BRCA2, and PALB2 Mutation Testing, see policy #1998051.
Policy/
Coverage:
Effective November 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults meets  member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes 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; 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.
 
* For 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.
 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx meets primary coverage criteria,  if tumor is unavailable in women with ovarian, fallopian tube, or primary peritoneal cancer when the patient meets criteria per the FDA label for treatment(s) for which this test has been approved as a companion diagnostic. [0239U]
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for germline NBN variants for ovarian cancer risk assessment in adults does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  For members with contracts without primary coverage criteria, testing for germline NBN variants for ovarian cancer risk assessment in adults is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults who do not meet the criteria above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  For members with contracts without primary coverage criteria, testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults who do not meet the criteria above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
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 does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx for any indication or condition not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  For members with contracts without primary coverage criteria, Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx for any indication or condition not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 15, 2022 through October 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults meets  member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes 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; 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.
 
* For 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.
 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx meets primary coverage criteria,  if tumor is unavailable in women with ovarian, fallopian tube, or primary peritoneal cancer when the patient meets criteria per the FDA label for treatment(s) for which this test has been approved as a companion diagnostic. [0239U]
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults who do not meet the criteria above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  
 
For members with contracts without primary coverage criteria, testing for BRIP1, RAD51C, and RAD51D variants for ovarian cancer risk assessment in adults who do not meet the criteria above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx for any indication or condition not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.  
 
For members with contracts without primary coverage criteria, Ovarian, Fallopian Tube, or Primary Peritoneal Cancer FoundationOneⓇ Liquid CDx for any indication or condition not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage
Rationale:
Molecular Testing for Variants Associated with Hereditary Ovarian Cancer in Unaffected Individuals in a Family at Risk of Epithelial Ovarian Cancer
 
Systematic Reviews
Suszynska et al reported a systematic review of variants identified in panels of breast and ovarian cancer-related genes (Suszynska, 2019). Results were reported for BRIP1, RAD51C, and RAD51D. The systematic review included studies published through July 2017 reporting on genetic test results of breast and ovarian cancer patients who were referred for evaluation by a multi-gene panel. The studies of panel results were used to calculate mutation frequencies by gene. As a control, population mutation frequencies were extracted from the Genome Aggregation Database. Fifteen studies included panels in ovarian cancer patients. In the ovarian cancer studies, 7099 patients were included in the analysis of BRIP1, 3791 patients were included in the analysis of RAD51C, and 3258 patients were included in the analysis of RAD51D. BRIP1, RAD51C, and RAD51D variants were identified in 1.06%, 0.55%, and 0.58% of ovarian cancer patients, respectively. The meta-analytic estimate odds ratio (OR) of the association between BRIP1, RAD51C, and RAD51D variants and risk of ovarian cancer was OR = 4.9 (95% CI, 3.7 to 6.4), OR = 4.2 (95% CI, 2.6 to 7.0), and OR = 7.3 (95% CI, 4.0 to 13.1). These mutations were not associated with breast cancer risk in this study.
 
In 2020, Suszynska and coworkers conducted a meta-analysis to more precisely estimate the ovarian cancer risk associated with BRIP1, RAD51C, and RAD51D mutations (Suszynska. 2020). A total of ~29,400 ovarian cancer patients from 63 studies were included in the analysis of 443 variants through September 2019. Cases were compared to ~116,000 controls from the Genome Aggregation Database. Family history of ovarian cancer was variable in ovarian cancer cases and unknown in the control population. Analyses of BRIP1, RAD51C, and RAD51D included 22494, 23802, and 22787 cases, respectively. BRIP1, RAD51C, and RAD51D variants were identified in 0.89%, 0.63%, and 0.41% of ovarian cancer patients, respectively. The meta-analytic OR of the association between BRIP1, RAD51C, and RAD51D variants and risk of ovarian cancer was OR = 4.94 (95% CI, 4.07 to 6.00), OR = 5.59 (95% CI, 4.42 to 7.07), and OR = 6.94 (95% CI, 5.10 to 9.44). Cumulatively, 1.93% of ovarian cancer patients had a mutation in 1 of the 3 genes compared with 0.35% in population controls. The study authors estimate that these genes may contribute to 10% of hereditary ovarian cancer cases.
 
Observational Studies
A number of studies reporting relative risks (RR) or ORs for the association between BRIP1, RAD51C, and RAD51D and ovarian cancer were identified. Studies from single-country samples are described first followed by multinational collaborative efforts. Four studies reported penetrance estimates (Ramus, 2015; Song, 2015; Loveday, 2012; Loveday, 2011). Study designs included family-based case-control and population-based or multicenter case-control (Loveday, 2012; Loveday, 2011; Lhotova, 2020; Weber-Lassalle, 2018; Norquist, 2016; Ramus, 2015).
 
Single-Country Samples
Lhotova et al evaluated the genetic predisposition for ovarian cancer (OC) with multi-gene panel testing for 219 genes in 1333 Czech patients with OC and 2278 population-matched controls, which included testing for BRIP1, RAD51C, and RAD51D (Lhotova, 2020). From 1333 analyzed OC patients, 1045 (78.4%) women were diagnosed with OC only and 288 (21.6%) women were diagnosed with double primary tumors, including breast cancer (BC) (210 patients; 15.8%) or other tumors (78 patients; 5.9%). Approximately half of patients (47.6%) had a negative family cancer history. Germline mutations for BC and OC predisposition genes were detected in 32.0% of patients compared to 2.5% of controls. Mutations in RAD51C and RAD51D conferred high OC risk (OR > 5) and mutations in BRIP1 were associated with moderate risk (OR = 3.5) in this study. Mutations in BRIP1, RAD51C, and RAD51D prevailed in patients diagnosed with OC only.
 
Weber-Lasalle et al assessed the role of deleterious, truncating loss-of-function (LoF) BRIP1 variants in breast and ovarian cancer predisposition (Weber-Lasalle, 2018). Well-characterized index patients with breast cancer (BC) (N=6341), OC (N=706), and geographically matched controls of German descent were analyzed via next-generation sequencing according to German Consortium for Hereditary Breast and Ovarian Cancer inclusion criteria for germline testing and tested negative for BRCA1/2 mutations. Of 706 index OC patients, 523 patients affected by OC only demonstrated a higher risk of OC (OR, 23.12; 95% CI, 13.08 to 40.88) compared to 183 patients affected by both OC and BC (OR, 8.10; 95% CI, 1.96 to 33.53). OC index cases with a family history of OC (N=190) demonstrated a higher risk of OC (OR, 32.21; 95% CI, 15.06 to 68.90) compared to 421 OC index cases with a family history of BC only (OR, 16.01; 95% CI, 7.82 to 23.76). A significant association was also noted in the subgroup of patients with late-onset OC. BC index patients with a family history of OC only (N=1027) demonstrated a significantly increased risk of OC (OR, 3.59; 95% CI, 1.43 to 9.01; P = 0.0168) whereas BC index patients with a family history of BC only did not (OR, 1.42; 95% CI, 0.70 to 2.90; P = 0.3030). The authors conclude that an elevated BRIP1 mutation prevalence in the BC subgroup was driven by the occurrence of OC within families.
 
Lilyquist et al included an analysis of 7768 Caucasian adult ovarian cancer cases of European ancestry who were referred to a single clinical testing laboratory for hereditary multi-gene panel testing (Lilyquist, 2017). Testing for 19 genes including BRIP1, RAD51C, and RAD51D was conducted. A family history of breast or ovarian cancer was reported in 44.9% and 15.1% of study subjects, respectively. Ovarian cancer cases were compared to non-Finnish European controls from the Exome Aggregation Consortium dataset. A 5-fold or greater increased risk of ovarian cancer was found for BRIP1, RAD51C, and RAD51D. A significantly higher rate of pathogenic/likely pathogenic (P/LP) variants was detected for BRIP1 and RAD51D in cases diagnosed at age 60 or later. In a subset of 3830 cases without a personal or family history of breast cancer, the association between BRIP1, RAD51C, and RAD51D and increased risk of ovarian cancer was RR = 4.08 (2.59 to 6.13), RR = 4.80 (2.93 to 7.42), and RR = 7.02 (2.58 to 15.27).
 
Kurian et al reported the association between pathogenic variants and breast or ovarian cancer using a commercial laboratory database of 95561 women tested clinically for hereditary cancer risk using a multi-gene panel that included BRIP1, RAD51C, and RAD51D (Kurian, 2017). Although the country is not stated, the patients underwent testing between 2013 and 2015 performed at a Clinical Laboratory Improvement Amendments laboratory and thus will be assumed to include patients from the U.S. Cases were women with a single diagnosis of breast or ovarian cancer. Controls were women from the same database (i.e., being tested for hereditary cancer) with no cancer history at the time of genetic testing. No family history of breast or ovarian cancer was reported in 72% of ovarian cancer cases. The multivariable models for ovarian cancer risk are reported here. Among 5,020 ovarian cancer cases, 36 (0.72%), 32 (0.64%) and 9 (0.18%) variants were found in BRIP1, RAD51C, and RAD51D genes. The association between these genes and ovarian cancer were adjusted for age, ancestry, personal and family cancer histories, and Lynch and adenomatous polyposis colon cancer syndromes. No significant association was found between these genes and an increased risk of breast cancer.
 
Norquist et al evaluated 1915 women diagnosed with ovarian cancer from the University of Washington gynecologic tissue bank (N=570) and from the Gynecologic Oncology Group (GOG) phase III clinical trials 218 (N=788) and 262 (N=557) (Norquist, 2016). Participants were not selected for age or family history. Mutation frequencies in cases were compared to population controls from the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP; N=4300) and the Exome Aggregation Consortium (ExAC; N=36276). Overall, 18% of ovarian cancer patients carried pathogenic germline mutations in genes associated with ovarian cancer risk of which 3.3% occurred in a BRCA-Fanconi anemia ovarian cancer-associated gene (eg, BRIP1, PALB2, RAD51C, RAD51D, or BARD1).
 
Loveday et al sequenced the full coding region and intron-exon boundaries of RAD51C in 1102 probands from breast-ovarian pedigrees and 30 unrelated index cases from ovarian only pedigrees (Loveday, 2012). Index cases were screened and negative for BRCA1/2 germline mutations. At least 97% of families were of European ancestry. A total of 449 index cases had a personal history of ovarian cancer, of which 149 also had breast cancer and 683 index cases had breast cancer only. The study also included 272 unrelated individuals with ovarian cancer from the Royal Marsden Hospital with unknown BRCA1/2 status and family histories. Index cases were compared to 1156 population-based controls from the 1958 Birth Cohort Collection in Great Britain. A total of 12 mutations were identified among 1132 familial cases compared to 1 mutation in the control population (P = 0.009). Among unselected ovarian cancer cases, 3 mutations were identified. In this study, no evidence for an association with breast cancer was found (RR, 0.91; 95% CI, 0.45 to 1.86; P = 0.8).
 
Loveday et al identified 8 inactivating RAD51D mutations in 911 unrelated probands from 1648 breast-ovarian cancer families compared with 1 inactivating mutation in 1060 controls from the 1958 Birth Cohort Collection (P = 0.01) (Loveday, 2012).  Breast cancer-only pedigrees were associated with 737/911 index cases. Three mutations were identified in 59 pedigrees with 3 or more cases of ovarian cancer (P = 0.0005). While a significant association b between RAD51D and ovarian cancer was found, no significant association with breast cancer was determined in this study (RR, 1.32; 95% CI, 0.59 to 2.96).
 
Multinational Samples
Song et al sequenced and analyzed germline DNA for RAD51C and RAD51D variants from 3429 women with invasive EOC and 2772 controls from 4 population-based case-control studies, 1 clinic-based case-control study, 1 familial OC series of cases and matched controls, and 2 familial OC registries (Song, 2015). Overall, 91.4% of OC cases were unselected for family history. Additionally, 2000 unaffected women with BRCA1/2-negative status from the UK Familial Ovarian Cancer Screening Study (UKFOCSS) were also analyzed. Eligible participants were women age 35 or older with an estimated lifetime risk of ovarian cancer ≥ 10% on the basis of a family history of ovarian and/or breast cancer and/or the presence of known predisposing germline gene mutations (eg, BRCA1, BRCA2, and MMR genes) in the family. A significantly greater rate of unaffected UKFOCSS participants were found to carry RAD51C (N=7) and RAD51D (N=5) deleterious variants compared to controls (P < 0.001). RAD51 mutation carriers were significantly more likely than non-carriers to have a family history of ovarian cancer (P < 0.001).
 
Ramus et al analyzed 3374 case patients and 3487 control patients from 8 ovarian cancer case-controls studies, 1 familial ovarian cancer registry in the U.S., and 1 case series to establish whether rare protein-truncating variants in BRIP1 are associated with an increased risk of OC in populations of European origin (Ramus, 2015). An additional 2167 unaffected women who had previously tested negative for BRCA1 and BRCA2 variants that participated in the UKFOCSS between June 2002 and September 2010 were also studied. Sequencing results were available for 3236 EOC cases and 3431 control patients and 2000 women from the UKFOCSS. UKFOCSS subjects demonstrated a prevalence rate of 0.60% (12/2000; P = 8 x 10-4). A family history of breast, ovarian, or both cancers was reported in 6.7%, 10% and 13.3% of BRIP1 carriers and 8.4%, 13.1%, and 18.8% of non-carriers.
 
Specific Variants
Rafnar et al identified approximately 16 million sequence variants through whole-genome sequencing of 457 Icelanders (Rafnar, 2011). Results were imputed to 41675 Icelanders and their families through chips identifying single nucleotide polymorphisms (SNP). A rare (0.41% allelic frequency) frameshift mutation in the BRIP1 gene, c.2040_2041insTT, was detected in 656 individuals and found to confer an increase in ovarian cancer risk (OR, 7.95; P = 5.65 x 10-13). A cohort of 11741 Icelandic subjects with cancer and 3913 controls was assessed for this variant which was found to significantly increase risk of OC (OR, 8.13; 95% CI, 4.74 to 13.95; P = 2.8 x 10-14) and increase risk of cancer in general, reducing lifespan by 3.6 years (95% CI, 1.5 to 5.7).
 
Kushnir et al sequenced 206 high risk Jewish women with breast and/or ovarian cancer (BC=190; OC=14; BC+OC=2) for RAD51C mutations (Kushnir, 2017). Thirty-eight percent of women were of Ashkenazi origin (N=78). No truncating mutations were detected. Two missense mutations were found, p.Ile144Thr and p.Thr287Ala, previously described in Iraqi and mixed ethnicity Balkan-North African cases, respectively. Although some prediction algorithms suggest these variants may be possibly pathogenic, neither of these sequence variants leads to a variant with an unequivocal deleterious effect. The 2 missense variants were not identified in individuals with Ashkenazi origin.
 
Catucci et al genotyped 149 high-risk women with breast (N=127) and ovarian (N=22) cancer from cancer prone families of Ashkenazi origin for BRIP1 mutations (Catucci, 2012). Cases were negative for BRCA1/2 mutations. One novel missense mutation (p.Ala745Thr) and 2 previously described missense mutations (p.Val193Iso and p.Ser919Pro) were detected. No truncating mutations were identified. These variants were not detected in any of 93 healthy Ashkenazi cancer-free controls. A subgroup analysis for cases with ovarian cancer was not reported. The relationship between missense variants in BRIP1 and ovarian cancer risk is unclear (Balmana, 2016).
 
Variant Classificaton
Valid variant classification is required to assess penetrance and is of particular concern for low prevalence variants. Due to heterogeneous application of variant classification tools and/or in silico algorithms and widespread use of next generation sequencing, the frequency of specific variants in the clinical validity studies is likely low and difficult to assess. While there are guidelines for variant classification, the consistency of interpretation among laboratories is of interest. Balmaña et al examined the agreement in variant classification by different laboratories from tests for inherited cancer susceptibility from individuals undergoing panel testing (Balmana, 2016). The Prospective Registry of Multiplex Testing registry is a volunteer sample of patients invited to participate when test results were provided to patients from participating laboratories. From 518 participants, 603 variants were interpreted by multiple laboratories and/or found in ClinVar. Discrepancies for BRIP1 and RAD51C were reported. Of 33 BRIP1 results with multiple interpretations, 3 (9%) had at least 1 conflicting interpretation, 2 (6%) had a conflicting interpretation as pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS), and all conflicting classifications were missense mutations. Of 26 RAD51C results with multiple interpretations, 1 deletion mutation (4%) had a conflicting interpretation as a P/LP variant and a VUS and 12 (46%) missense mutations had a conflicting interpretation as benign/likely benign variants and VUS. Given the nature of the sample, there was a significant potential for biased selection of women with either reported variants of uncertain significance or other uncertainty in interpretation. In addition, the majority of discrepancies were confined to missense variants. It is therefore difficult to draw conclusions concerning the frequency of discrepant conclusions among all tested women.
 
Direct evidence of clinical utility limited to women with BRIP1, RAD51C, and RAD51D variants was not identified.
 
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Studies of women at high risk based on family history alone or in those with BRCA1 and BRCA2 variants are relevant to the clinical utility of BRIP1, RAD51C, and RAD51D testing given the penetrance estimates for these genes and their related molecular phenotype ("BRCAness"). Interventions to decrease ovarian cancer risk in asymptomatic high-risk women include chemoprevention (eg, oral contraceptives) and prophylactic risk-reducing surgery (eg, bilateral risk-reducing salpingo-oophorectomy [RRSO]). Screening interventions for ovarian cancer (eg, transvaginal ultrasound [TVUS], serum cancer antigen-125 [CA-125] testing) have shown to have limited clinical benefit on health outcomes (Domchek, 2010; Nelson, 2019; Ramus, 2015). Combined surveillance methods have been associated with an unneeded rate of diagnostic surgery of 55% and significantly higher cancer-related distress (Nelson, 2019).https://www.evidencepositioningsystem.com/_w_e21c647a0c4dc4b1b17bd84d81d029720ff12bb0d51ac45a/bcbsa_html/BCBSA/html/_blank Ovarian cancer screening has not been shown to reduce mortality among women at risk of hereditary disease (Tung, 2016). Case-control studies have demonstrated that oral contraceptive use reduces the risk of ovarian cancer by 45% to 50% in BRCA1 mutation carriers and by 60% in BRCA2 mutation carriers, with decreasing risk with longer duration of oral contraceptive use (NCCN, 2019).
In women at high risk of hereditary ovarian cancer, including BRCA1 and BRCA2 carriers, evidence supports a reduction in subsequent ovarian cancer after risk-reducing oophorectomy. Decision analyses have modeled the impact of risk-reducing surgery on age-specific gains in life expectancy. Schrag et al examined penetrance magnitudes in the range of those estimated for BRIP1, RAD51C, and RAD51D variants and found that a 30-year old BRCA carrier with an expected 5% cumulative risk of ovarian cancer by age 70 would gain an expected 0.3 years with a prophylactic oophorectomy (Schrag, 1997). The age-specific gain in life expectancy increases to 1 year for a 30-year old with 20% risk. Furthermore, among 30-year old women, oophorectomy may be delayed by 10 years with little loss of life expectancy (see Table 9). The Markov model assumed that women receiving prophylactic oophorectomy received hormone replacement therapy until the natural age of menopause and that prophylactic oophorectomy did not have an effect on the probability of breast cancer. In an updated evidence report and systematic review for the US Preventative Services Task Force, Nelson and coworkers determined that risk-reducing salpingo-oophorectomy decreased ovarian cancer incidence by 69% to 100% and all-cause mortality by 55% to 100% among high-risk women and BRCA mutation carriers (Nelson, 2019).
Tung et al developed a counseling framework for moderate-penetrance cancer-susceptibility mutations associated with ovarian cancer risk, including BRIP1, RAD51C, and RAD51D genes (Tung, 2016). Cumulative lifetime risk (CLTR) (ie, penetrance) was modeled as the risk of cancer experienced by an individual between birth and the age of 80 years, utilizing average relative-risk multipliers from the population-based case-control studies of Ramus et al and Song et al (Ramus, 2015; Song, 2015). Population age-specific incidence rates were obtained from the 2008-2012 SEER cancer statistics for all races. This model is limited by assuming a constant relative risk over the lifetime, utilizing average relative risks despite higher or lower risks seen with truncating vs missense mutations, lack of generalizability to non-US populations, and failure to capture individual modifications in risk from genetic and non-genetic factors. The estimated CLTR associated with mutations in BRIP1, RAD51C, and RAD51D were found to approximate to the lower end of ovarian-cancer risk estimates for BRCA2 mutation carriers. Due to the limited benefits of ovarian cancer screening, Tung and coworkers propose a counseling framework for BRIP1, RAD51C, and RAD51D mutation carriers that warrants consideration of RRSO. However, as RRSO is not routinely recommended for women whose only ovarian cancer risk factor is an affected first-degree relative, it is argued that a woman's cumulative risk of ovarian cancer should therefore approach or exceed the LTR of a woman with an affected BRCA-negative first degree relative (approximately 2.64%) before they are offered RRSO. The model indicates the risk threshold is crossed between the ages of 50-55 years for BRIP1, RAD51C, and RAD51D carriers, thus deferring RRSO until a woman is perimenopausal or postmenopausal may be reasonable. However, women with mutations in these genes who also have a family history of ovarian cancer in a first-degree relative may cross the risk threshold earlier. Current society guidelines recommend discussing RRSO around 45-50 years of age or earlier based on specific family history of an earlier onset of OC (NCCN, 2019).
Additionally, how variant detection affects penetrance estimates compared with family history alone is of interest. As with BRCA variants, model-based estimates allow estimating risks for individual patient and family characteristics. The CanRisk tool, a web interface to BOADICEA v5, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, has been enhanced with a separate prediction model based on the BOADICEA methodology to include the effects of rare pathogenic BRCA1, BRCA2, BRIP1, RAD51C, and RAD51D variants on OC risk (University of Cambridge, 2020; Jervis, 2015; Lee, 2019).https://www.evidencepositioningsystem.com/_w_e21c647a0c4dc4b1b17bd84d81d029720ff12bb0d51ac45a/bcbsa_html/BCBSA/html/_blank To illustrate, a 30-year old woman whose BRCA1/2-negative mother was diagnosed with OC at age 50 and died at 52 has an estimated 10.4% risk of OC by age 80 compared to the average population risk of 1.3% in the United States; the risk increases to 12.6%, 16.7%, and 18.1% if the daughter carries a BRIP1, RAD51C, or RAD51D variant, respectively. If the mother carries a RAD51D variant and the daughter's variant status is unknown, she has an estimated risk of 14.1% by age 80; this risk increases to 18% if both mother and daughter test positive for a RAD51D variant.
The enhanced BOADICEA and CanRisk tools which integrate the effects of rare variants in moderate and high penetrance genes have not been validated and are intended for research use only. Validated risk-prediction models for familial OC (eg, BOADICEA v3, BRCAPRO) currently assume that all familial aggregation to OC is due to BRCA1 and BRCA2 mutations.
Finally, in studies of women with a BRCA1/2 mutation who underwent RRSO, occult gynecologic carcinomas were identified in 4.5% to 9% of cases based on careful pathologic examination of the ovaries and fallopian tubes (NCCN, 2019). Although tubal intraepithelial carcinoma (TIC), hypothesized to serve as an early precursor lesion for serous ovarian cancers, appears to be more prevalent in BRCA carriers, TIC has also been documented in patients with serous carcinomas unselected for family history or BRCA status. Among high-risk women, RRSO may provide an opportunity for occult gynecologic cancer detection. An analysis of 966 RRSO procedures detected invasive or intraepithelial ovarian, tubal, or peritoneal neoplasms in 25 (2.6%) of patients (4.6% of BRCA1 carriers, 3.5% of BRCA2 carriers, and 0.5% of non-carriers; P < 0.001) (Sherman, 2014). In a study of asymptomatic Slovenian women with P/LP BRCA variants (N=145) and BRCA-negative high-risk status (N=10) (ie, at least 2 first- or second-degree relatives with ovarian cancer) who underwent RRSO from January 2009 to December 2015, 9 (5.8%) occult cancers were identified; 8 in BRCA1-positive women and 1 in a high-risk BRCA-negative woman (Gornjec, 2020).
Molecular Testing for Variants Associated With Hereditary Ovarian Cancer in Individuals Diagnosed With Epithelial Ovarian Cancer
Primary treatment of epithelial ovarian cancer involves unilateral or bilateral salpingo-oophorectomy (BSO) and comprehensive staging in patients desiring fertility. In surgical candidates where optimal cytoreduction is likely and fertility is not desired, hysterectomy and BSO, comprehensive surgical staging, and debulking surgery as needed is recommended. For poor surgical candidates or in individuals with a low likelihood of optimal cytoreduction, neoadjuvant therapy is recommended prior to interval debulking surgery with completion hysterectomy/BSO and cytoreduction (NCCN, 2020). Therefore, testing of BRIP1, RAD51C, and RAD51D variants may potentially inform therapy.
 
BRCA mutation status and/or genomic instability-based homologous recombination deficiency (HRD) inform the clinical utility of poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib, rucaparib, and niraparib) in women diagnosed with ovarian cancer, and U.S. Food and Drug Administration approved companion diagnostics that assess HRD for PARP inhibitors calculate genomic instability by measuring loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and/or large-scale state transitions (LST) using DNA isolated from tumor tissue specimens and do not presently test for gene variants other than BRCA1 and BRCA2. Beyond BRCA-mutated tumors, current HRD assays have not provided sufficient differentiation of patient response to PARP inhibitors (Konstantinopoulos, 2020). In a phase 3 trial of niraparib, PRIMA investigators stratified results for HRD/BRCA wild-type tumors and homologous recombination proficient (HRP) tumors and found an overlapping therapeutic benefit in both groups (HRD - HR, 0.5; 95% CI, 0.31 to 0.83; HRP - HR, 0.68; 95% CI, 0.49 to 0.94) (Gonzalez-Martin, 2019). In a phase 3 trial of rucaparib, ARIEL3 investigators reported results for BRCA wild-type tumors with low or high LOH and found an overlapping therapeutic benefit in both groups (LOH low - HR, 0.58; 95% CI, 0.40 to 0.85; LOH high - HR, 0.44; 95% CI, 0.29 to 0.66) (Coleman, 2017). Results in these studies were not stratified by non-BRCA HRD gene. Clinical trials of patients with non-BRCA HRD mutations including BRIP1, RAD51C, and RAD51D have suggested mechanisms that confer sensitivity and acquired resistance to PARP inhibitors and reported that platinum-based chemotherapy in combination with bevacizumab is effective and does not yield a significant difference in PFS and OS compared to patients with BRCA mutations (Kondrashova, 2017; Norquirst, 2018).
 
While these initial reports are encouraging, the use of BRIP1, RAD51C, and RAD51D variant status to guide maintenance and recurrence therapy continues to be elucidated in the clinical trial setting (eg, NCT04171700). In contrast to unaffected women at high familial risk of ovarian cancer, women diagnosed with ovarian cancer who undergo testing for BRIP1, RAD51C, and RAD51D variants do not yield clinically actionable results.
 
Practice Guidelines and Position Statements
 
American Society for Clinical Oncology
In 2019, the American Society for Clinical Oncology (ASCO) issued guidelines regarding germline and somatic tumor testing for women with epithelial ovarian cancer (EOC) (Konstantinopoulos, 2020). A systematic review evaluating 19 systematic reviews of observational data, consensus guidelines, and RCTs informed the guideline recommendations. The ASCO Expert Panel recommends that germline sequencing of BRCA1 and BRCA2 be performed in the context of a multi-gene panel. This multi-gene panel should, at minimum, additionally include RAD51C, RAD51D, BRIP1, MLH1, MSH2, MSH6, PMS2, and PALB2. For women who do not carry a germline pathogenic/likely-pathogenic BRCA1/2 mutation, somatic tumor testing for BRCA1/2 is recommended. The guideline recommendations state that women with EOC should be offered testing at the time of diagnosis as this has implications for therapeutic decision-making.
 
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines on genetic/familial high-risk assessment for breast and ovarian cancer (v.1.2020) review single-gene tests for BRIP1, RAD51C, and RAD51D (NCCN, 2019). The guidelines state that a number of genes, including but not limited to BRIP1, RAD51C, and RAD51D, may be included in a multi-gene test. However, the inclusion of a gene in the guidelines does not imply endorsement for or against multi-gene testing for moderate-penetrance genes. Based on estimates of lifetime risk of OC in carriers of pathogenic/likely pathogenic variants in BRIP1, RAD51C, or RAD51D from available studies, there appears to be sufficient evidence to justify consideration of risk-reducing salpingo-oophorectomy (RRSO). However, while the current evidence is insufficient to firmly recommend an optimal age for risk-reducing surgery, based on the limited evidence base, the guidelines recommend that a discussion regarding RRSO should be held around 45-50 years of age or earlier based on specific family history of an earlier onset of OC. While the guidelines state that these genes may be associated with a potential increase in triple-negative breast cancer (BC), there is currently insufficient evidence for BC risk management.
 
The NCCN guidelines on on epithelial ovarian cancer (v.1.2020) provide primary treatment recommendations for patients with stage IA-IV disease (NCCN, 2020). For those desiring fertility with stage 1A or IB disease, unilateral and bilateral salpingo-oophorectomy with comprehensive surgical staging are recommended, respectively. For stage IA-IV patients not desiring fertility where optimal cytoreduction is likely, hysterectomy and bilateral salpingo-oophorectomy are recommended in combination with debulking as needed. For surgical candidates, germline and somatic testing is recommended following surgery. For poor surgical candidates or those with a low likelihood of optimal cytoreduction, neoadjuvant therapy is recommended with genetic risk evaluation. The guidelines note that BRCA1/2 status may inform maintenance therapy. In the absence of a BRCA1/2 mutation, HRD status may guide therapy with PARP inhibitors.
 
Society of Gynecologic Oncology
In 2013, the Society of Gynecologic Oncology (SGO) issued a clinical practice statement with recommendations concerning salpingectomy for ovarian cancer prevention (SGO, 2013). For women who have BRCA1 or BRCA2 germline mutations, counseling regarding bilateral RRSO after completion of childbearing is recommended. For women who choose to delay or forego RRSO, counseling regarding risk-reducing salpingectomy when childbearing is complete is recommended, followed by oophorectomy at a future date, although data on the safety of this approach is limited. For women who are at average, population risk of ovarian cancer, risk-reducing salpingectomy should be considered with patients at the time of abdominal or pelvic surgery, hysterectomy, or in place of tubal ligation.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below.
 
Ongoing
NCT02489006
A Phase II, Open-Label, Randomized, Multi-Centre Study, of Neoadjuvant Olaparib in Patients With Platinum Sensitive Recurrent High Grade Serous Ovarian/Primary Peritoneal or Fallopian Tube Cancer (NEO)
Planned Enrollment: 71 Completion Date: Dec 2021(recruiting)
 
NCT04009148
Cascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome
Planned Enrollment; 300 Completion Date: Mar 2022 (recruiting)
 
NCT04171700a
A Phase 2 Multicenter, Open-label Study of Rucaparib as Treatment for Solid Tumors Associated With Deleterious Mutations in Homologous Recombination Repair Genes (LODESTAR)
Planned Enrollment: 220 Completion Date: May 2022 (recruiting)
 
NCT03119285
Genes Contributing to Hereditary Ovarian Cancer in Women and BRCA1/2 Wildtype Families
Planned Enrollment: 150 Completion Date: Jul 2023 (recruiting)
 
NCT03294343
Risk-Reducing Surgeries of Salpingo-oophorectomy With/Without Hysterectomy for Carriers With Mutation Genes of Hereditary Ovarian Cancer
Planned Enrollment: 600 Completion Date; Sep 2023 (recruiting)
 
NCT03992131a
A Phase 1b/2, Open-label, Parallel Arm Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in Combination With Other Anticancer Agents in Patients With a Solid Tumor (SEASTAR)
Planned Enrollment: 329 Completion Date: Mar 2024 (recruiting)
 
NCT04294927
TUBectomy With Delayed Oophorectomy as Alternative for Risk-reducing Salpingo-oophorectomy in High Risk Women to Assess the Safety of Prevention (TUBA-WISP II)
Planned Enrollment: 3000 Completion Date: Feb 2040 (recruiting)
 
NCT02760849
Women Choosing Surgical Prevention (WISP)
Planned Enrollment: 300 Completion Date: May 2042 (recruiting)
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The study by Lhotova et al included testing for NBN (Lhotova, 2020). In contrast to prior studies, NBN variants were associated with potentially increased risk of OC (OR = 3.5).
 
Lilyquist et al also included NBN in their review (Lilyquist, 2017). While the investigators found an elevated frequency of pathogenic alterations in NBN among OC cases, this outcome was only marginally significant after Bonferroni correction for the number of genes tested (RR = 2.03; 95% CI, 1.27 to 3.08; p =.004).
 
Kurian et al also included NBN in their revie w (Kurian, 2017). Among 5,020 OC cases, 17 (0.34%) variants were in NBN gene.
 
In the study by Norquist et al, the NBN gene was not more frequently mutated in women with OC (Norquist, 2016)
 
In the study by Ramus et al, no significant difference in NBN mutations was detected between cases and controls (p =.61) (Ramus, 2015).
 
Flaum et al conducted a case-control study of 3767 cases and 2043 controls to investigate the frequency of the BRIP1 c.1045G>C missense variant (Flaum, 2022). This variant was associated with a significantly increased risk of familial epithelial OC (OR = 140.8; 95% CI, 23.5 to 1723.0; p <.0001). This missense variant was considered of particular interest as its dominant-negative effect may confer higher risks than loss-of-function counterparts.
 
A post hoc exploratory analysis by ARIEL2 investigators found that alterations in RAD51C and RAD51D correlated with meaningful clinical activity of rucaparib similar to that of BRCA-positive high-grade OC (Swisher, 2021; Swisher, 2021).
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March  2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2022, it was reported that out of 10 EOC patients with RAD51C and RAD51D alterations enrolled in ARIEL3,60% derived exceptional benefit compared to patients harboring mutations in other non-BRCA homologous recombination repair genes (O'Malley, 2022). However, the relevance of these findings is unclear as only 3 of these patients had confirmed germline mutations.
CPT/HCPCS:
0102UHereditary 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])
0103UHereditary 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])
0131UHereditary 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)
0132UHereditary 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)
0134UHereditary 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)
0135UHereditary 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)
0239UTargeted genomic sequence analysis panel, solid organ neoplasm, cell free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations
81432Hereditary 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
81433Hereditary 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
References: American Cancer Society (ACS).(2022) Key Statistics for Ovarian Cancer. 2022; https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed July 25, 2022.

Flaum N, van Veen EM, Smith O, et al.(2022) Dominant-negative pathogenic variant BRIP1 c.1045G C is a high-risk allele for non-mucinous epithelial ovarian cancer: A case-control study. Clin Genet. Jan 2022; 101(1): 48-54. PMID 34585738

Kurian AW, Hughes E, Handorf EA, et al.(2017) Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women. JCO Precision Oncology 2017;1: 1-12.

Lhotova K, Stolarova L, Zemankova P, et al.(2020) Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer. Cancers (Basel). Apr 13 2020; 12(4). PMID 32295079

Lilyquist J, LaDuca H, Polley E, et al.(2017) Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. Nov 2017; 147(2): 375-380. PMID 28888541

Norquist BM, Harrell MI, Brady MF, et al.(2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. Apr 2016; 2(4): 482-90. PMID 26720728

Online Mendelian Inheritance in Man (OMIM).(2016) Johns Hopkins University, Baltimore, MD. MIM Number: 602667. October 11, 2016; https://omim.org/entry/602667. Accessed July 25, 2022.

Ramus SJ, Song H, Dicks E, et al.(2015) Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. Nov 2015; 107(11). PMID 26315354

Swisher EM, Kristeleit RS, Oza AM, et al.(2021) Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer. Gynecol Oncol. Dec 2021; 163(3): 490-497. PMID 34602290

Swisher EM, Kwan TT, Oza AM, et al.(2021) Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nat Commun. May 03 2021; 12(1): 2487. PMID 33941784
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