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

Homologous recombination deficiency (HRD) genomic instability score as ACMG/AMP evidence for *BRCA1/2* variant pathogenicity

This ENIGMA consortium project assesses, across 4,943 high-grade ovarian cancers (765 BRCA1/2 pathogenic variant carriers), whether the HRD genomic instability score (MyChoice HRD+ CDx assay) can serve as evidence for ACMG/AMP classification of BRCA1/2 variants. A high HRD-GIS status (≥42) yields a likelihood ratio of 3.03 favoring pathogenicity (supporting evidence), while a low score (LR 0.13) constitutes moderate benign evidence. Notably, 91% of BRCA-mutated tumors were HRD-GIS high versus 30% of wild-type tumors. This approach provides a quantified data point directly integrable into the classification framework, particularly for VUS.

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

This is an elegant use of a companion test already run routinely in onco-therapeutics to feed germline variant classification — a rare convergence between somatic and constitutional medicine. The likelihood ratio calibrated on the ACMG Bayesian model is immediately usable in classification meetings. The main contribution will be reclassification of BRCA1/2 VUS, a major bottleneck in genetic counseling, with no added analytical cost when HRD testing has already been performed.