BRCA1
Chr 17ADARBRCA1 DNA repair associated
Also known as: BRCAI, BRCC1, BROVCA1, FANCS, IRIS, PNCA4, PPP1R53, PSCP
The BRCA1 protein functions as an E3 ubiquitin ligase that facilitates DNA repair by forming polyubiquitin chains and coordinating cellular responses to DNA damage through homologous recombination. Heterozygous mutations cause autosomal dominant familial breast-ovarian cancer syndrome and increase susceptibility to pancreatic cancer, while biallelic mutations result in autosomal recessive Fanconi anemia complementation group S. The pathogenic mechanism involves loss of DNA repair capacity leading to genomic instability and increased cancer risk in the heterozygous state, or severe DNA repair deficiency causing bone marrow failure and developmental abnormalities in the homozygous state.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
BRCA1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
ScreenIng of Genetic Susceptibility Genes for Breast Cancer Patients in CHinese communiTies
RECRUITINGA Phase 1/1B Study of ST-01156, a Small Molecule RBM39 Degrader, in Patients With Advanced Solid Malignancies
RECRUITINGAssessing Clinical Features and Outcome of Breast Cancer in PALB2 Mutation Carriers: the Palbreast Study
RECRUITINGComprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation or a Homologous Recombination Deficiency (COMPRENDO
ACTIVE NOT RECRUITINGA Prospective Registry for Patients at High-Risk for Pancreatic Cancer
RECRUITINGPembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability
ACTIVE NOT RECRUITINGPhase Ib Study of Axatilimab in Combination With Olaparib in BRCA1/2 and PALB2- Associated Metastatic HER2-negative Breast Cancer
RECRUITINGCombination Therapy in Cancers With Mutations in DNA Repair Genes
RECRUITINGCanadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGPROMISE Registry: A Prostate Cancer Registry of Outcomes and Germline Mutations for Improved Survival and Treatment Effectiveness
RECRUITINGThe PLATINUM Trial: Optimizing Chemotherapy for the Second-Line Treatment of Metastatic BRCA1/2 or PALB2-Associated Metastatic Pancreatic Cancer
ACTIVE NOT RECRUITINGKPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II
RECRUITINGExternal Resources
Links to major genomics databases and tools