403: HRD-GIS Evidence for BRCA1/2 Variant Classification

Schnaiter et al et al., The American Journal of Human Genetics - Schnaiter et al. pooled Myriad MyChoice HRD+ CDx results from four cohorts (4,943 HGOC tumors) to test whether tumor HRD-related genomic instability scores (HRD-GIS) provide evidence for BRCA1 and BRCA2 variant classification under ACMG/AMP criteria. Key terms: homologous recombination deficiency, genomic instability score (HRD-GIS), BRCA1, BRCA2, MyChoice HRD+ CDx. Study Highlights:The authors analyzed 4,943 tumors (765 BRCApv, 4,178 BRCAwt) assessed with the MyChoice HRD+ CDx assay and found 91.0% of BRCApv tumors were GIShigh (≥42) versus 30.0% of BRCAwt. The pooled likelihood ratio (LR) that a variant is pathogenic in a GIShigh HGOC was 3.03 (95% CI: 2.88–3.19), mapping to supporting pathogenic evidence. Conversely, the pooled LR for GISlow (<42) was 0.13 (95% CI: 0.10–0.16), mapping to moderate benign evidence. Results were consistent across three cohorts but limited by assay type, cohort composition, and incomplete second-hit and germline/somatic data. Conclusion:HRD-GIS measured by the MyChoice HRD+ CDx assay in HGOC yields statistically robust evidence that can be applied within ACMG/AMP variant interpretation: GIShigh supports pathogenicity (supporting strength) and GISlow supports benign classification (moderate strength), potentially improving BRCA1/2 VUS resolution. Music:Enjoy the music based on this article at the end of the episode. Article title:Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity First author:Schnaiter et al Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.05.015 Reference:Schnaiter et al., 2026, The American Journal of Human Genetics 113, 1–8. https://doi.org/10.1016/j.ajhg.2026.05.015 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/hrd-gis-brca-variant-pathogenicity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-26. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's coverage of HRD-GIS mechanism, BRCA1/BRCA2 variant interpretation via ACMG/AMP LR framework, threshold 42 (GIShigh vs GISlow), cohort data (Marburg, NHS, Study 19, NOVA), the Myriad MyChoice HRD+ CDx assay, and discussed limitations (second hits, germline vs somatic, assay-specific validation).- transcript topics: HRD-GIS mechanism in HGOC; BRCA1/BRCA2 function and HRD; Genomic scar metrics: LOH, TAI, LST; GIS scoring threshold and GIShigh/GISlow; Likelihood ratio framework and ACMG/AMP evidence mapping; Cohort data and Myriad MyChoice HRD+ CDx validation QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- HRD-GIS is a composite of LOH, telomeric allelic imbalance (TAI), and large-scale state transitions (LST).- GIS high is GIS ≥ 42; GIS low is GIS < 42.- Dataset comprised 4,943 HGOC tumors (765 BRCApv, 4,178 BRCAwt...