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 (BRCApv) 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-GIShigh (≥42) or HRD-GISlow (<42) tumor status, and these LRs were mapped to ACMG/AMP evidence strength categories defined by Bayesian modeling. Across the pooled dataset of 4,943 tumors (765 BRCApv and 4,178 BRCA1 or BRCA2 wild type [BRCAwt]), 91.0% of BRCApv and 30.0% of BRCAwt tumors were HRD-GIShigh. The LR for a BRCA1 or BRCA2 variant being pathogenic in an HRD-GIShigh HGOC was 3.03 (95% confidence interval [CI]: 2.88-3.19), corresponding to supporting pathogenic evidence. Conversely, the pooled LR for a variant being pathogenic in an HRD-GISlow HGOC was 0.13 (95% CI: 0.10-0.16), corresponding to moderate benign evidence. The HGOC HRD-GIS determined by the MyChoice HRD+ CDx assay provides statistically robust evidence for BRCA1 and BRCA2 variant interpretation. This approach may refine variant classification, particularly for variants of uncertain significance, and enhance clinical decision-making in hereditary and tumor-based cancer risk assessment.