Clinical validation of genomic functional screen data: Analysis of observed BRCA1 variants in an unselected population cohort

Functional assessment of genomic variants provides a promising approach to systematically examine the potential pathogenicity of variants independent of associated clinical data. However, making such conclusions requires validation with appropriate clinical findings. To this end, here, we use variant calls from exome data and BRCA1-related cancer diagnoses from electronic health records to demonstrate an association between published laboratory-based functional designations of BRCA1 variants and BRCA1-related cancer diagnoses in an unselected cohort of patient-participants. These findings validate and support further exploration of functional assay data to better understand the pathogenicity of rare variants. This information may be valuable in the context of healthy population genomic screening, where many rare, potentially pathogenic variants may not have sufficient associated clinical data to inform their interpretation directly. Lab-based functional assays hold promise for predicting the pathogenicity of rare variants in populations. Schiabor Barrett et al. show that a functional assessment of BRCA1 gene variants distinguished individuals with increased rates of BRCA1-related cancers that mirrored published cancer rates in individuals with pathogenic BRCA1 variants detected by indication-based testing.