Hereditary Cancer Panel: Variant of Uncertain Significance in a Young Breast Cancer Patient
A 32-year-old woman is diagnosed with triple-negative breast cancer. She has no family history of breast or ovarian cancer. She undergoes a multigene hereditary cancer panel (including BRCA1, BRCA2, PALB2, CHEK2, ATM, etc.). The result shows a heterozygous missense variant in BRCA2 (c.1234A>G, p.Asn412Ser), classified as a variant of uncertain significance (VUS). The variant is absent from gnomAD, and in silico tools predict it to be damaging. The patient's tumor is tested for BRCA1/2 mutations and is negative. The patient asks whether she should have a bilateral mastectomy and whether her sister should be tested. The genetic counselor explains the VUS. The patient is anxious and wants definitive answers.
1. How should the VUS be managed clinically? What are the recommendations for the patient and her sister?
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A VUS in BRCA2 should not be used to make clinical management decisions. The patient's cancer treatment should be based on her tumor characteristics and guidelines for triple-negative breast cancer. For her sister, testing for the VUS is not recommended because it is not actionable. However, the sister should be counseled about her own risk based on family history (which is unremarkable) and general population risk. The patient should be offered participation in research studies to help classify the VUS. The VUS may be reclassified over time. The patient should not undergo bilateral mastectomy solely based on the VUS; however, her breast cancer diagnosis itself may warrant consideration of contralateral prophylactic mastectomy based on other factors (e.g., young age, triple-negative status). The genetic counselor should explain that the VUS does not confirm hereditary predisposition. The sister should not be tested for the VUS unless it is reclassified as pathogenic. If the sister has a strong family history, she should be managed based on that.
2. What evidence would be needed to reclassify this VUS as likely pathogenic or pathogenic? Describe the types of evidence and how they could be obtained.
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To reclassify the VUS, we need evidence from multiple sources:
- Population data: The variant is absent from gnomAD, which supports pathogenicity (PM2). However, absence in gnomAD is not sufficient; need to check for presence in affected individuals.
- Segregation: If additional family members with breast/ovarian cancer are found to carry the variant, co-segregation can be assessed (PP1). However, the family history is currently negative, so this may require testing extended relatives.
- Functional assays: Develop or use established functional assays for BRCA2 (e.g., homology-directed repair (HDR) assay, sensitivity to PARP inhibitors). If the variant impairs BRCA2 function, this supports pathogenicity (PS3).
- Case-control studies: Compare frequency of the variant in large cohorts of breast cancer cases vs controls. If enriched in cases, supports pathogenicity (PS4).
- Computational predictions: Already used (PP3), but these are weak.
- mRNA studies: If the variant affects splicing, RNA analysis could show aberrant splicing (PS3 or PVS1 if null).
- Tumor characteristics: The patient's tumor is triple-negative, which is consistent with BRCA2 pathogenicity, but not specific.
- Multifactorial likelihood models: Use tools like the BRCA1/2 likelihood ratios from co-segregation and pathology.
To reclassify, the variant would need to meet ACMG criteria for likely pathogenic (e.g., PS3 + PM2 + PP3, or PS4 + PM2). Currently, it meets PM2 and PP3 only, so it remains a VUS. The patient could be enrolled in a research study (e.g., ENIGMA, ClinVar) to contribute data.