Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity.

Homologous recombination deficiency (HRD)-driven genomic instability as an indicator of BRCA1/BRCA2 variant pathogenicity

Homologous recombination deficiency (HRD) guides platinum- and PARP-inhibitor-based therapies in high-grade ovarian cancer, but its value for BRCA1/BRCA2 variant classification under the ACMG/AMP framework had not been assessed. In this ENIGMA consortium project, four independent cohorts were pooled (4,943 tumours, including 765 pathogenic-variant carriers). The HRD genomic instability score was high in 91.0% of pathogenic-variant tumours versus 30.0% of wild-type tumours. The likelihood ratio for a pathogenic variant given high HRD was 3.03 (supporting pathogenic evidence) and 0.13 given low HRD (moderate benign evidence). The HRD score thus provides statistically robust evidence for variant interpretation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Repurposing an HRD test already run to guide treatment in order to refine BRCA1/BRCA2 variant classification is elegant and directly actionable, particularly for reclassifying VUS. Bayesian calibration onto the ACMG/AMP framework gives this criterion a formal place in classification reasoning. This contribution is immediately relevant to hereditary risk assessment and routine VUS triage.

Analysis by Dr Thibaut Benquey