BACKGROUNDDecoding the clinical impact of genetic variants is particularly important for precision medicine in cancer. Genetic screening of mainly patients with breast and ovarian cancer has identified numerous BRCA1/BRCA2 variants of uncertain significance (VUS) that remain unclassified owing to a lack of pedigrees and functional data.METHODSHere, we used CRISPR-Select - a technology that exploits unique inbuilt controls at the endogenous locus - to assess 54 rare ClinVar VUS located in the PALB2-binding domain of BRCA2. Variant deleteriousness was examined in the absence and presence of PARPi, cisplatin, or mitomycin C.RESULTSMarked functional deficiency was observed for variants in the exon 2 donor splice region (A22 = c.66A>C, A22 = c.66A>G, A22 = c.66A>T, and D23H) and Trp31 aa (W31G, W31L, and W31C), both critical for BRCA2 function. Moreover, T10K and G25R resulted in an intermediate phenotype, suggesting these variants are hypomorphic in nature. Combining our functional results with the latest ClinGen BRCA1/2 Variant Curation Expert Panel recommendations, we classified 49 of the 54 VUS as either likely benign (n = 45) or likely pathogenic (n = 4).CONCLUSIONTherefore, CRISPR-Select is an important tool for efficient variant clinical classification. Application of this technology in the future will ultimately improve patient care.FUNDINGDanish Cancer Society, Novo Nordisk Foundation, Sygeforsikring Danmark, Børnecancerfonden, Neye-Fonden, Roche, Novartis, Pfizer, AstraZeneca, MSD, and Daiichi Sankyo Europe GmbH.