The era of personalized cancer genetics is here, and it promises to improve diagnosis and treatment. Extensive sequencing efforts over the past few decades have revealed numerous cancer driver genes, which can be used to stratify patients by treatment options, prognosis, and overall lifetime risk of developing cancer. Two well-known examples are the BRCA genes (BRCA1 and BRCA2), which have germline allelic variants that predispose carriers to developing cancer. However, while many alleles of BRCA1 are known to be pathogenic, an even greater number are characterized as variants of unknown significance (VUS), whose contributions to lifetime cancer risk are undefined. Such VUSs are difficult to predict as benign or pathogenic, especially in proteins like BRCA1 with extensive disordered regions, where the effects of mutations are poorly captured by predictive algorithms. The implications are profound: treatment and prevention strategies hinge on the classification of BRCA variants, yet many patients still face uncertainty and life-altering decisions without sufficient functional data, underscoring the urgent need for experimental approaches to resolve the VUS problem.
In this ASPIRE award, Steven Boeynaems will address this need by building a complete sequence-to-function map of BRCA1. Using a newly developed cloning-and-screening platform, his lab will generate and assay an ultra-large library encompassing all possible BRCA1 missense variants, enabling pooled functional screens to classify their effects. In parallel, high-throughput microscopy will uncover the mechanisms by which pathogenic variants disrupt DNA repair processes, providing insight into how BRCA1 loss-of-function contributes to cancer. Together, these efforts will create a resource with clinical utility, allowing clinicians and patients to make informed decisions based on functional evidence rather than prediction alone. Beyond BRCA1, this work will establish a framework for scaling functional testing across other major cancer genes, paving the way toward truly actionable personalized medicine.