A Familial Variant of Uncertain Significance in a Cancer Susceptibility Gene
A 45-year-old woman with bilateral breast cancer (diagnosed at 38 and 44) undergoes a multi-gene hereditary cancer panel. Testing identifies a missense variant in PALB2 (c.3056C>T, p.Thr1019Ile) classified as a variant of uncertain significance. Her mother had breast cancer at 62; a maternal aunt had ovarian cancer at 58. The patient's sister, 42 and unaffected, wants testing to 'know her risk.' The laboratory offers single-site testing for the VUS. The patient asks whether her sister should be tested and whether the VUS 'counts' for her own treatment decisions.
1. Should the sister undergo single-site testing for the VUS?
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Generally no, for clinical purposes. Single-site testing for a VUS is not recommended because the result does not change management: a positive result does not confirm increased risk, and a negative result does not exclude a hereditary cause. Testing the affected relative (the patient) for the VUS in the context of a research or reclassification program is appropriate; testing the unaffected sister is not.
If the family has a strong history suggesting a hereditary syndrome and the panel was negative, the better path is referral to genetics for consideration of broader testing (e.g., RNA analysis, deletion/duplication, or research) and for the sister to be managed on family history. If the variant is later reclassified as pathogenic, the sister can then be tested and the result would be actionable.
The judgment: not offering a test just because it is technically available, and recognizing that a VUS result is not actionable in an unaffected relative.
2. How should the VUS affect the patient's own surgical and treatment decisions?
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A VUS should not be used to make treatment or surgical decisions (e.g., contralateral prophylactic mastectomy, PARP inhibitor eligibility, or oophorectomy) because it does not establish a pathogenic PALB2 variant. Management should be based on her personal cancer history and family history, not the VUS.
However, her bilateral breast cancer at 38 and 44 plus a family history of ovarian cancer is clinically significant independent of the VUS. She should be managed as high-risk based on phenotype, and the team should consider whether additional testing is warranted (e.g., reanalysis, RNA studies, or a research protocol). The VUS should be flagged for periodic reclassification review, since reclassification to pathogenic would change management.
Key point: phenotype drives management when genotype is uncertain.
3. What should the counselor tell the family about reclassification and follow-up?
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Explain that VUS classification can change as evidence accumulates, and that the laboratory should be contacted periodically (e.g., annually) for reclassification. The family should be encouraged to update contact information and to re-contact genetics if new cancers occur in the family, since segregation data can contribute to reclassification.
Also explain the limits: reclassification is not guaranteed, and the family should not defer appropriate screening while waiting. The sister should follow screening based on family history. Document the plan for recontact and the rationale for not testing the sister now.