Decoding the BRCA2 reversion principles underlying PARP inhibitor resistance

Abstract Reversion mutations that restore BRCA2 function represent a major mechanism of resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA2 -mutant cancers. Predicting these events could inform treatment strategies, identify patients at increased risk of acquiring PARPi resistance, and improve interpretation of secondary variants. Here, we use an isogenic cell system and CRISPR editing to define the principles governing BRCA2 reversion. We show that local sequence context dictates the spectrum of reversions, whereas domain architecture determines which events confer PARPi resistance. We characterize two routes of reversion that operate both within and across exons: DNA-level reading-frame restoration and transcript-level rescue via alternative splicing. Lastly, we identify distinct exon 11 reversion mechanisms, including large genomic deletions and recurrent splice isoforms predicted to remove all eight BRC repeats. These findings define a predictive code for BRCA2 reversion and PARPi resistance.