Gene Number: 672

Location: 17q21.31

Key Functions: DNA damage response, tumor suppression, cell cycle control

The BRCA1 (breast cancer type 1 susceptibility) gene stands as one of the most pivotal genetic sentinels safeguarding the human genome. It encodes a tumor suppressor protein that coordinates the repair of double-strand DNA breaks—arguably the most lethal form of genetic damage. Its proper function is indispensable for maintaining chromosomal stability, accurate cell division, and the suppression of oncogenic transformation.

At the genetic and molecular level, BRCA1 operates through homologous recombination (HR), a precise DNA repair mechanism that restores damaged sequences using an undamaged sister chromatid as a template. Upon DNA injury, BRCA1 is rapidly mobilized to the site of damage, forming complexes with BARD1, PALB2, and BRCA2 to facilitate the recruitment of RAD51 recombinase, which executes the strand invasion and repair process. These interactions illustrate the gene’s epistatic relationships within the broader DNA repair network—a key concept in the genetics of cancer susceptibility.

Beyond repair, BRCA1 also influences cell cycle checkpoints (particularly the G1/S and G2/M transitions), ensuring that cells do not proceed through division before genomic integrity is verified. Through chromatin remodeling and histone modification, it regulates the transcriptional response to stress and DNA damage. These functions make BRCA1 a central node in the genetic architecture of genomic maintenance.

From a genetic perspective, pathogenic variants in BRCA1—often inherited in an autosomal dominant pattern—lead to haploinsufficiency, where one defective allele undermines the overall repair capacity of the cell. This predisposes carriers to cumulative DNA damage, eventually overwhelming compensatory pathways. The best-known of these variants are frameshift and nonsense mutations that result in truncated, nonfunctional proteins.

Clinically, individuals with BRCA1 mutations face a markedly elevated risk of breast (up to 80%) and ovarian cancer (up to 60%), as well as prostate, pancreatic, and fallopian tube cancers. These mutations also show genotype–phenotype correlations, with certain allelic variants associated with earlier onset or more aggressive tumor subtypes, particularly triple-negative breast cancers.

From a therapeutic standpoint, BRCA1-deficient tumors exhibit a well-defined molecular vulnerability: they depend on alternative, error-prone repair mechanisms such as base excision repair, rendering them exquisitely sensitive to PARP inhibitors. This phenomenon, known as synthetic lethality, represents a landmark in genetically guided cancer therapy.

In the broader genetic landscape, BRCA1 exemplifies the principle of inherited genomic instability—how a single germline mutation can alter the trajectory of somatic evolution within tissues. It stands as both a clinical biomarker and a genetic cornerstone in understanding the interplay between DNA repair fidelity and cancer susceptibility.