Eliminating variants of uncertain significance in BRCA1, BRCA2 and beyond

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Abstract By current evidence, roughly one-third of all cancers are driven in part by germline variation. Genetic testing now enables individuals and their doctors to better understand and manage their genetic cancer risk. However, the effectiveness of these tests is limited by the many gaps in our knowledge about the clinical impact of individual variants. Even in the well-studiedBRCA1 and BRCA2 genes, 7280 of the 17156 variants currently in ClinVar are listed as “Variants of Uncertain Significance” (VUS). VUS test reports leave patients with anxiety, and often lead to clinical mismanagement: many doctors frequently recommend bilateral mastectomies for patients with uncertain variants, even though many of those variants will turn out to be benign. Genetic testing will not reach its potential while VUS test reports are still frequent, yet with global data sharing, novel functional screens, and integrative data analysis methods, we can envisage eliminating the VUS problem. We will produce methods for secure data sharing, and integrative analysis that leverages highly predictive modern functional assays. We will demonstrate these approaches on BRCA1 and BRCA2, while outlining their application to other high-penetrance cancer susceptibility genes. We will develop APIs to integrate this new knowledge into the ClinGen and CIViC repositories, to benefit the larger research community. Finally, we will extend the integrative data visualization of BRCA Exchange to additional genes implicated in breast, ovarian and colorectal cancers, which will ultimately benefit tens of thousands of cancer patients and previvors.