404: HRD-GIS refines BRCA1/2 variant classification in ovarian cancer

Schnaiter S et al., The American Journal of Human Genetics - Pooled analysis of four cohorts (4,943 tumors) using the Myriad MyChoice HRD+ CDx assay quantified how HRD-related genomic instability scores (HRD-GIS) predict BRCA1 and BRCA2 variant pathogenicity and mapped likelihood ratios to ACMG/AMP evidence strengths. Key terms: homologous recombination deficiency, HRD-GIS, BRCA1, BRCA2, ovarian cancer. Study Highlights:Schnaiter et al. pooled Myriad MyChoice HRD+ CDx results from four cohorts totaling 4,943 high-grade ovarian tumors to assess whether tumor HRD-GIS predicts BRCA1/2 variant pathogenicity. They observed 91.0% of BRCApv tumors were GIShigh versus 30.0% of BRCAwt tumors. The pooled likelihood ratio for a variant being pathogenic in a GIShigh tumor was 3.03 (95% CI 2.88–3.19), equivalent to supporting pathogenic evidence, while GISlow had a pooled LR of 0.13 (95% CI 0.10–0.16), equivalent to moderate benign evidence. Results apply to HGOC samples assessed with the MyChoice assay and may aid ACMG/AMP variant classification, with noted cohort and assay limitations. Conclusion:HRD-GIS determined by the MyChoice HRD+ CDx assay in HGOC provides supporting evidence for BRCA1/2 pathogenicity when GIShigh and moderate benign evidence when GISlow, supporting its integration into ACMG/AMP variant interpretation. 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 S Journal:The American Journal of Human Genetics DOI:10.1016/j.ajhg.2026.05.015 Reference:Schnaiter S., Santer F.R., Csanaky K.A., et al. Homologous recombination deficiency-driven genomic instability in ovarian cancer as an indicator of BRCA1 and BRCA2 variant pathogenicity. The American Journal of Human Genetics. 113, 1–8 (2026). 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-classification QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-30. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript sections describing BRCA1/BRCA2 biology, genomic scars (LOH, TAI, LSTs), GIS scoring with MyChoice HRD+ CDx, Bayesian/ACMG interpretation, cohort details, and clinical implications, comparing them to the original article.- transcript topics: BRCA1 and BRCA2 role in homologous recombination; Genomic scar signatures: LOH, telomeric allelic imbalance, large-scale state transitions; Genomic instability score (GIS) and Myriad MyChoice HRD+ CDx assay; Bayesian LR framework and ACMG/AMP variant interpretation; Cohort details: Marburg, NHS, Study 19, NOVA; limitations (germline vs somatic, HGOC focus); Clinical implications for BRCA variant classification and VUS 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...