Large-scale integration of functional assay data for the resolution of germline BRCA1 and BRCA2 variants of uncertain significance.

BRCA1/2

Germline BRCA1 and BRCA2 missense variants classified through harmonized integration of functional assay data, using assay-specific ClinGen interpretation guidelines

Widespread germline genetic testing has led to a marked increase in the detection of variants of uncertain significance in BRCA1 and BRCA2. The authors curated, harmonized and integrated functional data for 3247 BRCA1 and 6177 BRCA2 missense variants from multiple studies, converted into ordinal categorical variables, and applied assay-specific ClinGen guidelines to assign evidence for or against pathogenicity. Large case-control studies confirmed that benign and pathogenic variants categorized by this integrated functional framework are associated with low and high breast cancer risk, respectively. Integration of additional data sources resolved 80.1% of BRCA1 and 69.5% of BRCA2 variants of uncertain significance, and classified 6517 missense variants (2345 in BRCA1 and 4172 in BRCA2).

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

This is the kind of resource that concretely changes a laboratory's daily practice: a previously inconclusive BRCA1 or BRCA2 missense variant becomes classifiable in most cases, with direct consequences for surveillance and cascade testing. Validation by large case-control studies is the key argument, as it links the functional readout to clinical risk. The abstract specifies neither the final split between benign and pathogenic variants nor how these classifications will be made available to laboratories.

Analysis by Dr Thibaut Benquey