How to Order BRCA2 Mutation Testing
BRCA2 mutation testing should be ordered after genetic counseling and risk assessment, beginning with testing of an affected family member when possible, and should include complete sequencing of coding regions with techniques to detect large genomic alterations. 1
Step-by-Step Process for Ordering BRCA2 Testing
Step 1: Identify Appropriate Candidates for Testing
Testing should be offered to:
- All patients newly diagnosed with breast cancer age 65 or younger 1
- Patients over 65 with:
- Triple-negative breast cancer
- Personal or family history suggesting genetic predisposition
- Male breast cancer
- Ashkenazi Jewish ancestry
- Candidacy for PARP inhibitor therapy 1
- Individuals with family history meeting criteria:
- Three or more breast/ovarian cancer cases (at least one under 50)
- Two breast cancer cases under 40
- Male breast cancer with early-onset female breast cancer
- Breast and ovarian cancer in same patient 1
Step 2: Refer for Genetic Counseling
Before testing, patients should receive genetic counseling that includes:
- Detailed family history analysis (pedigree)
- Risk assessment for BRCA mutations
- Education about possible test results and implications
- Identification of the most appropriate family member to test first
- Discussion of screening and risk-reduction options 1
Step 3: Select the Appropriate Testing Strategy
The testing approach depends on family history:
- For families with known mutations: Order testing for the specific familial mutation 1
- For Ashkenazi Jewish patients: Begin with testing for the three common founder mutations 1
- For patients without known familial mutations: Order comprehensive testing including:
- Complete sequencing of coding regions
- Testing for large genomic rearrangements/deletions (using techniques like MLPA) 1
- Consider multi-gene panel testing: Include other cancer predisposition genes (PALB2, TP53, PTEN, STK11, CDH1) based on personal and family history 1
Step 4: Obtain Informed Consent
Ensure the patient understands:
- Benefits and limitations of testing
- Possible results (positive, negative, variant of uncertain significance)
- Implications for medical management
- Potential impact on family members 1
Step 5: Collect and Submit the Sample
- Blood sample is typically used (genomic DNA extracted from blood)
- Follow laboratory-specific requirements for collection and shipping
- Include relevant clinical information and family history with the test requisition 1
Step 6: Post-Test Counseling and Management
- Interpret results with the patient
- For positive results: Discuss risk-reduction strategies (surveillance, prophylactic surgery, chemoprevention)
- For negative results: Clarify if truly negative or uninformative-negative
- For variants of uncertain significance: Explain limitations in interpretation 1
Important Considerations
- Preferred testing strategy: When possible, begin testing with an affected family member who has the highest likelihood of carrying a mutation 1
- Comprehensive testing: Include techniques to detect large genomic alterations, which account for 2-12% of mutations 1
- Multi-gene panels: Consider testing for other cancer predisposition genes beyond BRCA1/2 based on personal and family history 1
- Timing: Testing should be considered once individuals have reached age 18 1
Common Pitfalls to Avoid
- Testing unaffected individuals first: When possible, always start with the family member most likely to carry a mutation 1
- Misinterpreting negative results: An uninformative-negative result (when no affected relatives have been tested) does not rule out hereditary risk 1
- Overlooking large genomic alterations: Ensure testing includes methods to detect these mutations 1
- Failing to consider other genes: BRCA1/2 account for only 5-10% of hereditary breast cancers; consider multi-gene panel testing 1, 2
- Neglecting post-test counseling: Interpretation of results is complex and requires professional guidance 1
By following these steps, clinicians can appropriately order BRCA2 mutation testing to identify individuals at increased risk for hereditary breast and ovarian cancer, allowing for enhanced surveillance and risk-reduction strategies that can significantly reduce morbidity and mortality.