A central focus of the BRIDGES project was to establish the validity and utility of personalized risk-based breast cancer prevention, and specifically of gene panel testing, within the clinical routine of high-risk Family Cancer Centers.

To this end, BRIDGES has completed the analysis of multigene panel sequencing of an exceptionally large case-control cohort with > 110,000 individuals. We estimated odds ratios for overall breast cancer and tumor subtypes, separately for protein-truncating and rare missense variants. We evaluated missense variant associations by protein-domain and clinical classification of pathogenicity.

The results identified nine genes as clinically most useful for inclusion on panels for breast cancer risk prediction and delineated their associated risks. Furthermore, we were able to demonstrate that (subsets of) missense variants are associated with risk for some genes.

Laboratory assays to support the pathogenic classification of variants of uncertain clinical significance (VUS) have been developed for all genes with good evidence for being associated with breast cancer. These assays were applied to many of the DNA variants identified by BRIDGES, both at the protein and the mRNA level. In addition, a novel in silico tool was developed with improved accuracy of variant classification relative to other publicly available tools. The results are being disseminated through ClinGen expert panels and through a new version of the commercial software tool Alamut™ Visual Plus.

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