Capital BlueCross BRIP1 RAD51 testing Coverage

Coverage criteria and clinical utility

Coverage summary and clinical utility distinctions by gene and clinical scenario

Testing in undiagnosed, at-risk individuals for BRIP1/RAD51C/RAD51D: Germline testing for BRIP1, RAD51C, and RAD51D in individuals without diagnosed epithelial ovarian cancer but in families at risk of hereditary ovarian cancer provides clinical validity and improved risk estimation compared to family history alone; evidence is sufficient to support that testing results in improved net health outcome when results would inform consideration of risk-reducing interventions (e.g., risk‑reducing salpingo‑oophorectomy).

Applies where family history or validated risk assessment indicates elevated risk; preventive intervention evidence is indirect from high‑risk/BRCA studies

Testing of first- or second-degree relatives to guide prophylactic surgery (BRIP1/RAD51C/RAD51D): Testing an affected first‑ or second‑degree relative with a personal history of epithelial ovarian cancer to identify a familial BRIP1, RAD51C, or RAD51D pathogenic variant is supported to guide prophylactic decision‑making in undiagnosed relatives and reduces uninformative negative results.

Preferentially test relatives with early‑onset, bilateral, or multiple primaries to maximize chance of an informative result

NBN testing in at-risk undiagnosed individuals: Evidence for NBN germline variants shows a 2‑ to 3.5‑fold increased ovarian cancer risk in some studies but inconsistent mutation frequency and no reported penetrance estimates; national guidelines have not recommended risk‑reducing interventions for NBN carriers and evidence is insufficient to demonstrate improved net health outcome for testing to guide prophylactic surgery.

Testing and prophylactic surgery not supported by sufficient evidence; clinical validity not established

Testing in individuals with diagnosed ovarian cancer: For individuals with diagnosed ovarian cancer, direct evidence of clinical utility for germline testing of BRIP1, RAD51C, RAD51D, and NBN to guide treatment decisions is lacking; current therapeutic applications (e.g., HRD‑guided therapy) have not been stratified by these non‑BRCA HRD genes and are under investigation, so evidence is insufficient to show improved net health outcome for treatment guidance.

May inform familial risk assessment but is not proven to change treatment outcomes

Medically necessary testing

Covered when ALL of the following are met per policy adoption/adoption notes and BCBSA alignment

Primary criteria: Testing is considered medically necessary for BRIP1, RAD51C, and RAD51D when policy criteria adopted from BCBSA are met; NBN has an investigational statement noted in the policy history.

Policy history documents adoption of BCBSA criteria and addition of an NBN investigational statement (see policy history).

National guideline panels have not recommended risk-reducing interventions (for example, prophylactic bilateral salpingo-oophorectomy or other prophylactic surgery) based solely on identification of NBN germline variants because available studies show inconsistent mutation frequency, no reliable penetrance estimates, and insufficient data to define absolute ovarian cancer risk. As noted in the evidence summary, NBN variants have been associated with a 2- to 3.5-fold increased risk in some studies, but this signal has not been consistently observed across case-control comparisons and therefore guidelines defer management to family-history–based approaches rather than gene-directed prophylactic surgery.

An earlier review and the policy history characterized the use of germline testing to direct treatment for an individual already diagnosed with ovarian cancer as investigational. The policy history documents that testing to guide treatment for a diagnosed individual was noted as investigational when the policy was adopted and retained in subsequent updates.

Germline testing of BRIP1, RAD51C, RAD51D, and NBN in individuals with diagnosed ovarian cancer is considered to have insufficient evidence to demonstrate improved net health outcomes when used to guide treatment decisions. Direct evidence of clinical utility for therapy selection or maintenance in this population was not identified, and studies of homologous recombination deficiency or treatment response were not stratified by these non-BRCA genes.

Policy history notes that the approach of using germline testing exclusively to guide treatment for a diagnosed individual was described as investigational. The record of adoption and updates indicates that this investigational characterization was applied to this clinical use and retained when NBN was later added with an investigational statement.

Indications considered medically necessary

Germline testing to support prophylactic decision-making (BRIP1, RAD51C, RAD51D)

Indication: Germline testing for BRIP1, RAD51C, and RAD51D is covered in individuals without diagnosed epithelial ovarian cancer who have a family history or validated risk assessment indicating increased risk and when results would inform consideration of risk‑reducing interventions.

Evidence supports improved risk estimation versus family history alone and potential to inform prophylactic surgery decisions.

Affected-relative testing to inform at-risk relatives: Testing an affected first‑ or second‑degree relative with a personal history of epithelial ovarian cancer to identify a familial BRIP1, RAD51C, or RAD51D pathogenic variant is covered to guide prophylactic decision‑making for undiagnosed relatives.

Testing a relative with early‑onset, bilateral, or multiple primaries is recommended to maximize informative results.

Limitations—NBN: Germline testing for NBN in undiagnosed, at‑risk individuals is not supported as medically necessary because penetrance estimates are not established and national guidelines do not recommend risk‑reducing interventions based solely on NBN variants.

Who is eligible for testing

Coverage is determined using the member's specific benefit plan and clinical criteria in this policy; there are no additional top-level eligibility nodes beyond those specified in the coverage criteria. Providers should follow the policy criteria for gene- and scenario-specific medical necessity when assessing eligibility.

A detailed family history is an important factor in determining eligibility for germline testing. The policy highlights use of a multigenerational pedigree or validated risk tools (for example, BRCAPRO) and lists relevant ICD-10 family-history diagnosis codes (such as Z80.41, Z80.49, and Z80.8) that reflect family history of ovarian or other genital malignancies as considerations when assessing testing appropriateness.

No additional top-level eligibility requirements were specified in the provided segments beyond family-history–based considerations and the scenario-specific coverage criteria described elsewhere in this policy.

The provided document segments do not specify any required prior testing (for example, tumor testing or other molecular assays) that must be completed before ordering germline testing. The policy does recommend testing an affected first- or second-degree relative first when the goal is to identify a familial variant to inform prophylactic decisions, but it does not mandate prior laboratory tests as a precondition for ordering germline analysis.

Provider responsibilities, documentation, and billing

Note

Relative-first testing preferred

When genetic testing is being used to inform consideration of prophylactic surgery for hereditary ovarian cancer risk, test a first- or second-degree relative with a personal history of epithelial ovarian cancer (EOC) first whenever possible. Testing an affected relative (particularly one with early-onset disease, bilateral disease, or multiple primaries) increases the likelihood of identifying an informative pathogenic familial variant and reduces uninformative negative results or non-actionable variants of uncertain significance. Identification of a known familial variant enables targeted testing in at-risk relatives and more precise risk estimates to guide preventive interventions.

Preferred strategy: perform testing on first- or second-degree relative(s) with personal history of EOC before testing unaffected at-risk family members.
Prioritize relatives with early-onset, bilateral, or multiple primary ovarian cancers for highest diagnostic yield.
Use identified familial pathogenic variants to offer single-variant targeted testing to at-risk relatives when available.

Documentation Required

Benefit plan governs coverage

Procedure, CPT, and diagnosis codes

Procedure codes mentionedmixed

0102U	Proprietary/other molecular pathology procedure codes listed in policy
0103U	Proprietary/other molecular pathology procedure codes listed in policy
0131U	Proprietary/other molecular pathology procedure codes listed in policy
0132U	Proprietary/other molecular pathology procedure codes listed in policy
0134U	Proprietary/other molecular pathology procedure codes listed in policy
0135U	Proprietary/other molecular pathology procedure codes listed in policy
81432	CPT — Molecular pathology procedure code listed
81433	CPT — Molecular pathology procedure code listed

Procedure codes mentioned (alternate phrasing)mixed

No codes listed

Procedure codes (unlisted)CPT

81479

Unlisted molecular pathology procedure code

ICD-10 diagnosis codesICD-10

C48.0	Malignant neoplasm of retroperitoneum
C48.1	Malignant neoplasm of specified parts of peritoneum
C48.2	Malignant neoplasm of peritoneum, unspecified
C48.8	Malignant neoplasm of overlapping sites of retroperitoneum
C56.1	Malignant neoplasm of right ovary
C56.2	Malignant neoplasm of left ovary
C56.3	Malignant neoplasm of bilateral ovaries
C56.9	Malignant neoplasm of unspecified ovary
C57.00	Malignant neoplasm of unspecified fallopian tube
C57.01	Malignant neoplasm of right fallopian tube

1–10 of 15

1/2

Listed Procedure/CPT CodesCPT

0102U	Procedure code listed in policy
0103U	Procedure code listed in policy
0131U	Procedure code listed in policy
0132U	Procedure code listed in policy
0134U	Procedure code listed in policy
0135U	Procedure code listed in policy
81432	Procedure/CPT listed in policy
81433	Procedure/CPT listed in policy

Other Procedure CodesCPT

81479

Unlisted molecular pathology procedure

Associated ICD-10 CodesICD-10

C48.0	Malignant neoplasm of retroperitoneum
C48.1	Malignant neoplasm of specified parts of peritoneum
C48.2	Malignant neoplasm of peritoneum, unspecified
C48.8	Malignant neoplasm of overlapping sites of retroperitoneum
C56.1	Malignant neoplasm of right ovary
C56.2	Malignant neoplasm of left ovary
C56.3	Malignant neoplasm of bilateral ovaries
C56.9	Malignant neoplasm of unspecified ovary
C57.00	Malignant neoplasm of unspecified fallopian tube
C57.01	Malignant neoplasm of right fallopian tube

1–10 of 15

1/2

Billing Rule

Benefit plan determines coding application and coverage

Reiterate that coverage and application of coding are controlled by the member's benefit plan; listing codes in the policy does not guarantee coverage or payment.

Items and indications not covered

Germline testing of NBN for the purpose of guiding prophylactic surgery or for use as a sole predictor of individual ovarian cancer risk is not supported due to insufficient evidence. Although some studies report a 2- to 3.5-fold increased risk associated with NBN variants, inconsistent mutation frequency across studies and absent penetrance estimates prevent reliable risk stratification; consequently, national guidelines have not endorsed gene-directed prophylactic interventions for NBN carriers. In addition, using BRIP1, RAD51C, RAD51D, or NBN testing in individuals with diagnosed ovarian cancer to direct therapy lacks direct evidence of clinical utility and is therefore considered not medically necessary for treatment guidance.

The policy history explicitly documents that an investigational statement for NBN testing was added during policy updates. This investigational designation is reflected in the adoption notes and subsequent minor reviews recorded in the policy history.

Key definitions

Penetrance — definition and relevance

DefinitionPenetrance is the risk conferred by a pathogenic variant or the proportion of individuals with the variant expected to develop cancer; lifetime risk metrics (e.g., cumulative lifetime risk, remaining lifetime risk) vary in calculation and presentation.

ModifiersPenetrance can be modified by environmental factors and by family history, which is an important modifier for low- and moderate-penetrance genes.

Gene-specific examplesBRCA1 carriers: estimated lifetime ovarian cancer risk ~36%–63%; BRCA2 carriers: ~10%–27%, illustrating how penetrance differs by gene and variant.

Calculation variability (actionable)No consensus exists on how to calculate lifetime risk (CLTR vs. defined-age risk vs. remaining lifetime risk); this impacts guideline thresholds and counseling — use validated models and clearly state which metric is used.

Clinical relevancePenetrance informs clinical decision-making about risk-reducing interventions (e.g., prophylactic surgery) and helps interpret the magnitude of risk from identified pathogenic variants.

Background and evidence summary

Penetrance refers to the proportion of individuals with a pathogenic variant who are expected to develop cancer and varies by gene, specific variant, environmental exposures, and family history. BRIP1, RAD51C, and RAD51D are described as moderate-to-high penetrance genes for ovarian cancer with evidence supporting application of preventive interventions in appropriate high-risk families. In contrast, NBN has limited and inconsistent evidence for increased ovarian cancer risk and lacks published penetrance estimates; this uncertainty is a key factor in recommendations to manage NBN carriers based on family history rather than gene-specific prophylactic measures.

OpenPayer

Molecular testing for germline variants associated with ovarian cancer (BRIP1, RAD51C, RAD51D, NBN)