BRCA1

BRCA1 is a human tumor suppressor gene that encodes the BRCA1 protein, a large nuclear protein involved in maintaining genomic stability. The BRCA1 gene is located on chromosome 17q21 and spans about 80 kilobases with 24 exons. The BRCA1 protein is about 1,863 amino acids long and contains an N-terminal RING finger domain that provides E3 ubiquitin ligase activity, and C-terminal BRCT repeats that mediate phosphoprotein interactions. Through these domains BRCA1 participates in DNA damage sensing and repair, particularly homologous recombination, as well as transcriptional regulation and chromatin remodeling. BRCA1 forms complexes with other proteins such as BRCA2, PALB2, and RAD51 to repair double-strand breaks.

Germline pathogenic variants in BRCA1 substantially increase lifetime risk of breast and ovarian cancers and are inherited in an autosomal dominant manner with high penetrance. BRCA1-associated breast cancers are frequently triple-negative and may be more aggressive, though responses to DNA-damaging chemotherapy and to PARP inhibitors have improved outcomes. In addition to inherited risk, somatic BRCA1 mutations can occur in tumors, contributing to homologous recombination deficiency.

Management for BRCA1 mutation carriers includes enhanced cancer surveillance (e.g., annual MRI and mammography), risk-reducing surgeries such as prophylactic mastectomy or salpingo-oophorectomy, and consideration of PARP inhibitors or platinum-based chemotherapy for affected cancers. Population studies have identified founder mutations in certain groups, notably Ashkenazi Jews, with examples including 185delAG and 5382insC.