BRCA1

HIGH

BRCA1 DNA repair associated

Chromosome: 17q21.31

Gene Overview

BRCA1 encodes a tumor suppressor protein essential for homologous recombination (HR) DNA double-strand break repair. Germline loss-of-function mutations confer high lifetime risk of breast cancer (up to 72%) and ovarian cancer. BRCA1 forms complexes with PALB2, BRCA2, and RAD51 to promote error-free HR; deficiency leads to genomic instability and reliance on error-prone repair. BRCA1 also regulates transcription, cell cycle checkpoints, and centrosome function. Expression is cell-cycle regulated, peaking in S and G2 phases. Mutations cluster in the RING and BRCT domains. Carriers may have increased sensitivity to DNA-damaging agents including radiation.

Molecular Function

  • homologous recombination
  • DNA double-strand break repair
  • transcriptional regulation
  • ubiquitin ligase activity

Protein class: tumor suppressor

Regulatory Annotation

Promoter activity: E2F-responsive elements; p53 and estrogen receptor binding sites.

Enhancer associations: Tissue-specific regulation in breast epithelium.

Methylation sensitivity: BRCA1 promoter methylation silences expression in subset of sporadic breast cancers.

eQTL tissues: breast, ovary

Tissue Expression Context

breastTPM range: 3-12GTEx vv8
ovaryTPM range: 2-10GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

BRCA1 loss impairs HR repair; accumulated DNA damage and replication stress drive malignant transformation; PARP inhibitors exploit synthetic lethality in BRCA-deficient cells.

BRCA1-deficient cells hypersensitive to PARPi; olaparib approved for BRCA-mutant breast cancer.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Miki Y, et al. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. doi:10.1126/science.8035792
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Tutt A, et al. (2010). Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer. Lancet Oncology. doi:10.1016/S1470-2045(10)70012-2