Direct-to-Consumer Genetic Testing Results: A Patient with a BRCA1 Variant
A 45-year-old woman presents to her primary care physician with a report from a direct-to-consumer (DTC) genetic testing company. The report states she has a pathogenic variant in BRCA1 (c.68_69delAG, also known as 185delAG). She has no personal history of cancer, but her mother had breast cancer at 50 and her maternal aunt had ovarian cancer at 55. The DTC report is based on a saliva sample and uses a genotyping array, not sequencing. The patient is anxious and wants to know if she should have a prophylactic mastectomy. The physician is unsure about the validity of the DTC result and refers her to a genetic counselor. The genetic counselor orders clinical testing (sequencing and deletion/duplication analysis of BRCA1/2). The clinical test confirms the same BRCA1 variant. The patient's mother is deceased, but her aunt is alive and has not been tested.
1. What are the limitations of DTC genetic testing, and why was confirmatory testing necessary?
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DTC genetic testing has several limitations:
- Analytical validity: DTC tests often use genotyping arrays that may not detect all variants, including large deletions/duplications or rare variants. The 185delAG is a common founder mutation, so it may be included on the array, but the test may not be comprehensive.
- Clinical validity: DTC tests may not be validated for clinical use; the association between the variant and disease may be based on limited evidence.
- Clinical utility: DTC reports may not provide adequate counseling or interpretation; they may not account for family history or other risk factors.
- Regulatory oversight: DTC tests are not subject to the same stringent regulations as clinical tests (though FDA oversight is increasing).
Confirmatory testing in a CLIA-certified laboratory is necessary because:
- The DTC result may be a false positive or false negative.
- Clinical testing uses validated methods (sequencing and deletion/duplication analysis) that are more comprehensive.
- The clinical test provides a definitive result that can guide management.
In this case, the clinical test confirmed the variant, so the result is valid. However, without confirmation, it would be inappropriate to make clinical decisions based on DTC results alone.
2. What are the implications of the confirmed BRCA1 variant for the patient and her family? What management options should be discussed?
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The confirmed BRCA1 pathogenic variant (185delAG) confers a high lifetime risk of breast cancer (up to 80%) and ovarian cancer (up to 40-50%). Management options include:
- Enhanced surveillance: Annual breast MRI and mammography starting at age 25-30; transvaginal ultrasound and CA-125 for ovarian cancer (though efficacy is debated).
- Risk-reducing surgery: Bilateral prophylactic mastectomy (reduces breast cancer risk by >90%) and risk-reducing salpingo-oophorectomy (RRSO) recommended between ages 35-40 and 40-45, depending on guidelines. The patient is 45, so RRSO is recommended.
- Chemoprevention: Tamoxifen or other agents may be considered for breast cancer risk reduction.
- Family testing: The patient's aunt should be offered genetic testing for the familial variant. If the aunt tests positive, she should be managed accordingly. If negative, her risk is based on family history. The patient's children (if any) have a 50% chance of inheriting the variant; they should be offered testing at adulthood.
- Reproductive options: Preimplantation genetic testing or prenatal testing if desired.
The patient should be counseled about the psychological impact and the importance of shared decision-making. Prophylactic mastectomy is a personal choice; some women opt for surveillance instead. The genetic counselor should provide support and resources.