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

ABSTRACT: 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,

SUBMITTER: Bose M 

PROVIDER: S-EPMC12165785 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature