BRCA2 contains 8 BRC repeats in its middle region, which are involved in binding to RAD51 at resected DNA double-strand breaks (DSBs) (Bork et al. 1996, Wong et al. 1997, Venkitaraman 2002). Some BRCA2 missense mutations reported in cancer have been shown to impair BRCA2 binding to RAD51.BRCA2 G1529R mutant, involved in familial breast cancer, has a missense mutation that affects the fourth BRC repeat of BRCA2 (BRC4). The BRC4 construct which harbors the G1529R substitution shows 20-fold reduced binding to RAD51 relative to the wild type BRC4 (Chen et al. 1999). CHEK1 phosphorylation sites are preserved in BRCA2 G1529R mutant, but the phosphorylation is not shown as it has not been tested.BRCA2 mutant BRCA2 G1529E is annotated as candidate mutant for the loss of RAD51 binding as it has been reported in cancer, is predicted to be pathogenic and involves the same amino acid residue as the functionally characterized BRCA2 G1529R mutant.The C-terminal RAD51 interaction site, TR2, binds to RAD51 filaments and protects them from disassembly (Davies et al. 2007). TR2 is essential for the replication fork stabilization function of BRCA2 but dispensable for homology-directed repair (Schlacher et al. 2011). BRCA2 S3291A mutant, generated by directed mutagenesis, is unable to bind to RAD51. This mutant has not been reported in cancer but is documented as a BRCA2 allele in the ClinGen Allele Registry (Pawliczek et al. 2018).
Loss of function of BRCA2 mutants (RAD51 binding):SEM1 [nucleoplasm]