A Family History That Does Not Fit the Test Result
A 48-year-old man presents with a strong family history: his mother had breast cancer at 42, his maternal aunt had ovarian cancer at 55, and his sister was diagnosed with triple-negative breast cancer at 38. He himself is healthy. He requests 'the BRCA test' and says he wants to know for his two daughters. A multi-gene panel is ordered and returns negative for pathogenic variants in BRCA1, BRCA2, and other high-penetrance genes. He is relieved but his sister insists 'there must be a gene.' He asks whether his daughters should be tested and whether he can be told he is 'clear.'
1. How do you interpret the negative panel in the context of this family history, and what are the limits of the test?
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Reasoning:
A negative panel is not a negative family history. The family pattern (early breast, ovarian, triple-negative breast cancer) is highly suggestive of hereditary breast/ovarian cancer. A negative result may reflect:
- a variant in a gene not on the panel,
- a large deletion/duplication not detected,
- a variant in a regulatory region,
- a phenocopy or chance clustering,
- a yet-undiscovered gene.
The affected sister is the best person to test. Testing an unaffected man has lower yield. If the sister has not been tested, her testing (including deletion/duplication analysis) is more informative. If she carries a variant, he can be tested for that specific variant.
Do not say he is 'clear.' Say the test did not find a cause; his family history still warrants risk assessment.
Quantify risk: Use a validated model (e.g., a family-history-based risk calculator) to estimate his daughters' and his own risk, and discuss surveillance based on family history.
Document the plan for reanalysis as panels expand.
2. What do you tell him about testing his two daughters (ages 16 and 22)?
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Key points:
- No predictive testing of minors for adult-onset conditions when there is no childhood intervention. The 16-year-old should not be tested. The 22-year-old can decide for herself after counselling.
- There is no identified familial variant to test for, so daughter testing would be panel-based and have a low prior probability of a positive result, while still carrying VUS risk.
- Surveillance based on family history may be appropriate for adult daughters regardless of genetic testing; discuss with a high-risk clinic.
- Psychosocial framing: The daughters may feel pressure. Offer them independent counselling.
- Recontact: If the sister is tested and a variant is found, the family can be offered targeted testing.