BRCA2

BRCA2, or breast cancer susceptibility gene 2, is a human gene that encodes the breast cancer type 2 susceptibility protein. It functions as a tumor suppressor and plays a central role in the repair of DNA double-strand breaks by homologous recombination. Pathogenic variants in BRCA2 markedly increase lifetime risk of breast and ovarian cancer and are associated with elevated risks for pancreatic, prostate, and male breast cancers. The BRCA2 gene is located on chromosome 13q12.3.

The BRCA2-encoded protein is large, containing multiple functional motifs, including BRC repeats that bind RAD51 and a C-terminal DNA-binding domain with OB folds. BRCA2 facilitates homologous recombination by loading and regulating RAD51 on resected DNA, promoting strand invasion, and helping to protect replication forks from degradation. It also interacts with PALB2, linking BRCA1- and BRCA2-mediated DNA repair pathways in the nucleus.

Genetics and inheritance: BRCA2 variants are typically inherited in an autosomal dominant pattern with high penetrance, and familial testing is used to assess risk in relatives. Not all variants confer the same level of risk, and variants of uncertain significance are commonly identified in genetic testing.

Clinical implications and therapy: Cancers arising in BRCA2 mutation carriers often exhibit sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, such as olaparib, due to synthetic lethality. BRCA2 status informs prognosis and treatment decisions in breast, ovarian, pancreatic, and prostate cancers. In carriers, enhanced surveillance and consideration of risk-reducing strategies may be recommended, depending on individual risk factors and family history.