Characterization of BRCA1 ring finger variants of uncertain significance
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The majority of pathogenic mutations in BRCA1 result in a truncated protein. Although most missense changes in BRCA1 are of unknown functional significance, a handful of deleterious missense mutations have been identified. The majority of these occur in splice sites or highly conserved protein domains. Previously, we developed a predictive model, VUS Predict, to classify BRCA variants of uncertain significance as neutral or deleterious. It uses evolutionary prediction algorithms together with clinical information from cancer pathology reports and BRCA genetic testing results. Because of the higher probability that missense changes occurring in conserved BRCA1 domains are of pathogenic significance, we identified all individuals in our cohort who had been tested for BRCA1 and BRCA2 mutations who had missense changes in the BRCA1 ring finger domain and sought to classify those changes. We applied VUS Predict to three previously uncharacterized variants and four missense changes known to be deleterious. Two variants, L22S and T37K, were predicted to be deleterious and one variant, K45Q, was predicted to be neutral by VUS Predict. The mutations C39R, C44Y, C44S, and C61G were confirmed as deleterious.
KeywordsBRCA1 Variants of uncertain significance Ring finger domain Mutation characterization
Funding for this study was provided by the Ohio State University Comprehensive Cancer Center. We thank the OSU Clinical Cancer Genetics Program for ascertainment of patients to this study. Caroline Craven and Molly Means were instrumental in obtaining patient medical records and clinical information. We thank Andrew Spearman for his work in developing the prediction model used for this study.
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