Classifying Variants of Uncertain Significance associated with breast cancer

The identification of genetic, environmental and lifestyle factors that contribute to breast cancer susceptibility has had a marked impact on breast cancer prevention, early detection and treatment. Interventions for carriers of pathogenic and likely pathogenic (PLP) variants in breast cancer susceptibility genes include surgical, medical or lifestyle risk reducing treatments that can significantly reduce cancer risk. Currently, only a limited number of variants in these genes are classified as PLP and genomic testing predominantly targets women with a strong family or personal history of breast or ovarian cancer. A major clinical challenge is that >50% of variants in cancer predisposition genes are currently classified as variants of uncertain significance (VUS). Most VUS’s are missense variants, and the functional impact and clinical significance of these variants is not obvious. The high number of VUS’s limit the utility of population genomic screening and are a major obstacle for patients and clinicians. Using high throughput functional screens, we developed a robust, cost and time efficient strategy to build libraries that contain every possible variant in a cancer susceptibility gene and to experimentally measure the function of these variants. In this project, we will obtain a comprehensive map of functional variants in genes associated with one of the high and moderate breast cancer risk. We will implement these findings in variant classification rules by working with clinical variant curation expert panels and engagement with our network of clinicians (including genetic counsellors and clinical geneticists). Using large scale CRISPR screens and by systematic profiling of expression changes associated with pathogenic variants, we will identify exploitable interventions associated with PLP variants. This will enable future strategies for variant specific treatment and prevention. The findings will have an immediate impact on preventing cancer and a longer-term impact via the next-generation development of precision cancer treatments.