A prioritization framework for BRCA1/2 variants of uncertain significance identified by comprehensive genomic profiling - PubMed
4 hours ago
- #BRCA1/2
- #variant prioritization
- #genomic profiling
- Comprehensive genomic profiling (CGP) enables broad detection of clinically relevant genomic alterations in cancer.
- BRCA1/2 variants of uncertain significance (VUS) pose a challenge in clinical implementation.
- A study analyzed 2172 CGP tests from Hiroshima University Hospital and affiliated institutions in Japan.
- From 526 BRCA1/2 variants, 153 were classified as VUS.
- A prioritization framework using in silico predictors and functional evidence narrowed VUS to 10 candidates.
- Functional analysis of BRCA2:c.67 G > C (p.D23H) demonstrated exon 2 skipping, indicating loss of function.
- Clinical observations from patients with this variant aligned with homologous recombination deficiency.
- The study presents a proof-of-concept framework for prioritizing BRCA1/2 VUS in real-world CGP testing.
- The approach integrates in silico predictors with functional evidence for systematic variant assessment.
- The framework may be applicable to variant assessment in other hereditary cancer predisposition genes.