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

Homologous recombination deficiency (HRD) drives oncogenesis and therapeutic vulnerability in high-grade ovarian cancer (HGOC). While HRD testing is widely used to guide platinum- and especially poly(ADP-ribose) polymerase (PARP)-inhibitor-based therapies, its potential to provide evidence for BRCA1 and BRCA2 variant classification under the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) framework has not been assessed. In this Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium project, a literature review identified four independent HGOC cohorts reporting details on both BRCA1 and BRCA2 pathogenic variant (BRCA pv ) status and HRD-related genomic instability scores (HRD-GISs), all determined by the Myriad MyChoice HRD+ CDx assay. Likelihood ratios (LRs) were calculated to assess the probability that a BRCA1 or BRCA2 variant is pathogenic with a given HRD-GIS high (≥42) or HRD-GIS low (