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...