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.
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