Precision screening facilitates clinical classification of BRCA2-PALB2 binding variants with benign and pathogenic functional effects

Understanding the clinical impact of genetic variants is essential for advancing precision medicine in cancer. In particular, genetic screening of patients with breast and ovarian cancers often identifies numerous BRCA1/BRCA2 variants classified as "variants of uncertain significance" (VUS). These VUS remain unclassified due to a lack of familial data and functional assessments. Accurately interpreting these variants is crucial for clinical decision-making and selecting targeted therapies, such as PARP inhibitors (PARPi) and chemotherapy. In this study, we utilized CRISPR-Select, a cutting-edge technology that enables the analysis of genetic variants at the endogenous locus with built-in controls, to assess 54 rare VUS located in the PALB2-binding domain (PBD) of BRCA2.