The BRCA Exchange Knowledgebase for Clinical Cancer Genetics

PROJECT SUMMARY / ABSTRACT Heritable Breast, Ovarian, Pancreatic and Prostate (HBOP) cancers arise from pathogenic variation in cancer susceptibility genes, including BRCA1 and BRCA2. The average woman in the United States faces a 12% lifetime risk of breast cancer, but this number rises to roughly 66% for women who carry pathogenic variants in the BRCA1 or BRCA2 genes. These variants also present a 44% lifetime risk of ovarian cancer, compared to a 1.5% risk for women on average. Individuals who carry a pathogenic BRCA variant can manage their cancer risk clinically, often avoiding cancer entirely, but these clinical interventions are not available to all individuals at risk. The majority of observed BRCA variants are Variants of Uncertain Significance (VUS), individually rare yet collectively common variants for which there is insufficient evidence for clinical classification. Additionally, one-fourth of the BRCA variants in ClinVar have conflicting classifications. Sharing knowledge to promote accurate variant classification is key to reducing the burden of these heritable cancers. BRCA Exchange is the world’s largest public source of knowledge on variation in BRCA1 and BRCA2, aggregating variants from repositories including ClinVar, gnomAD and LOVD, and annotating them with pathogenicity evidence selected by the ENIGMA research consortium on HBOP Cancers and the ClinGen ENIGMA (BRCA1 and BRCA2) Variant Curation Expert Panel. This resource is visited by more than 3,000 distinct users per month worldwide, with data incorporated into major cancer research platforms including SOPHiA Genetics’ Alamut and the Barcelona Biomedical Genomics Lab’s Cancer Genome Interpreter. We seek funding to maintain and expand BRCA Exchange to leverage and support new progress in clinical genomics. We will 1) refactor the database to promote expansion while leveraging emergent variant annotation standards, 2) leverage new open source resources to expand the data integration pipeline sustainably, 3) continue formalizing the knowledgebase governance, 4) share provisional assignments of the ACMG variant evidence codes to promote VCEP-compliant variant curation, 5) share research datasets to leverage and support new scientific progress in HBOP variation, and 6) expand the scope to share variants for seven related genes for which there is now abundant and growing clinical knowledge but no effective knowledgebase.