Gene Number: 675

Location: 13q13.1

Key Functions: DNA repair via homologous recombination, tumor suppression, genomic stability maintenance

The BRCA2 (breast cancer type 2 susceptibility) gene is a central guardian of genomic integrity, closely allied with BRCA1, yet functionally distinct in its molecular execution of DNA double-strand break repair. It encodes a large nuclear protein that serves as a mediator and stabilizer of the homologous recombination (HR) process—a precise repair mechanism vital for the correction of replication-associated DNA damage.

At the mechanistic level, BRCA2 acts as the scaffold for RAD51 loading onto single-stranded DNA at the site of damage. Through a series of BRCA2–RAD51 interaction domains known as BRC repeats, it ensures the accurate pairing and exchange of homologous DNA strands. This process restores damaged DNA with high fidelity, thereby preventing mutagenic repair and chromosomal rearrangements that would otherwise precipitate tumorigenesis.

BRCA2 functions in tight cooperation with BRCA1 and PALB2, forming a hierarchical network of tumor suppressor proteins. While BRCA1 senses DNA damage and initiates repair signaling, BRCA2 executes the repair itself, guiding the RAD51 nucleoprotein filament assembly necessary for recombination. This division of labor reflects an epistatic relationship—mutations in any of these genes can disrupt the same repair pathway and produce overlapping clinical phenotypes.

From a genetic standpoint, pathogenic BRCA2 variants are inherited in an autosomal dominant fashion with incomplete penetrance, meaning that individuals who carry one defective allele are predisposed, though not guaranteed, to develop cancer. Most disease-causing mutations are frameshift, nonsense, or splice-site variants that result in truncated proteins incapable of supporting homologous recombination. The result is a cellular environment prone to genomic instability, where cumulative DNA errors accelerate malignant transformation.

Clinically, BRCA2 mutations confer high lifetime risks of several cancers, including breast (45–70%), ovarian (10–20%), prostate, pancreatic, and male breast cancer—a distinctive hallmark differentiating BRCA2 from BRCA1. The tumor spectrum of BRCA2 carriers tends to feature hormone receptor–positive subtypes more frequently than BRCA1-associated cancers, though both genes share an elevated susceptibility to aggressive, early-onset malignancies.

In the molecular oncology landscape, BRCA2 deficiency defines a “homologous recombination deficiency” (HRD) phenotype, now central to precision oncology. Tumors harboring such defects are highly sensitive to PARP inhibitors and DNA-damaging agents like platinum compounds, as these therapies exploit the tumor’s compromised repair machinery—an example of synthetic lethality in practice. Beyond oncology, BRCA2’s role extends into meiosis, ensuring accurate chromosomal segregation in germ cells—underscoring its evolutionary importance in maintaining genetic fidelity across generation.

In summary, BRCA2 stands as a molecular cornerstone of genomic preservation, its activity bridging the realms of repair biology, hereditary genetics, and targeted therapy. Mutations in this gene not only reshape cancer risk profiles but also represent a paradigm for understanding how defects in the DNA repair machinery can dictate both disease development and therapeutic response.