Large-scale integration of functional assay data for the resolution of germline BRCA1 and BRCA2 variants of uncertain significance
In brief
Integrated assay data resolve 80% of BRCA1 and 70% of BRCA2 uncertain variants
By harmonizing functional assay results with other evidence, researchers resolved 80.1% of BRCA1 and 69.5% of BRCA2 variants previously labeled uncertain, and classified 6,517 missense variants overall. Case-control data linked variants classified as benign or pathogenic to low or high breast cancer risk, respectively; whether this framework improves clinical decisions and patient outcomes remains to be established.
- Journal
- American journal of human genetics (Q1)
- Published
- 12 October 2026
- Study design
- Case-control study
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Paulo C M Lyra, Samuel Brito, Michael Parsons, Chunling Hu, Thales C Nepomuceno, Nam Phuong Nguyen, et al.
- PMID
- 42863474
- DOI
- 10.1016/j.ajhg.2026.09.013
Why clinicians should know about it
- Picked for Genetics (clinical) (paper of the day, 15 October 2026): Functional assay integration resolves BRCA VUSs
Abstract
Carriers of BRCA1 and BRCA2 pathogenic variants are at a significantly elevated risk for several cancers. Widespread germline genetic testing has led to a significant increase in the detection of variants of uncertain significance (VUSs) in these genes. To assess variant pathogenicity, we curated, harmonized, and integrated functional data for 3,247 BRCA1 and 6,177 BRCA2 missense variants derived from BRCA1/2 functional assays. Functional results were harmonized across studies by converting data into ordinal categorical variables. We applied ClinGen variant interpretation guidelines for each assay to assign evidence for or against pathogenicity. Final evidence criteria for each variant were obtained through the integration of results from different assays, and large case-control studies confirmed that benign and pathogenic variants categorized using the integrated functional framework are associated with low and high risk for breast cancer, respectively. Next, we integrated additional sources of data, leading to resolution of 80.1% of BRCA1 VUSs and 69.5% of BRCA2 VUSs and classification of 6,517 (2,345 in BRCA1 and 4,172 in BRCA2) missense variants.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.