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.
Primary Disease Associations & Inheritance
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 (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 70 | 0 | 27 | 0 | 97 |
Likely Pathogenic | 15 | 0 | 8 | 0 | 23 |
VUS | 5 | 176 | 24 | 4 | 209 |
Likely Benign | 0 | 11 | 60 | 69 | 140 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 4 | |||
| Total | 90 | 187 | 120 | 73 | 474 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View 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.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
SHARON: A Clinical Trial for Metastatic Cancer Using Chemotherapy and Patients' Own Stem Cells
RECRUITINGA Phase 1/1B Study of ST-01156, a Small Molecule RBM39 Degrader, in Patients With Advanced Solid Malignancies
RECRUITINGNiraparib + Dostarlimab In BRCA Mutated Breast Cancer
ACTIVE NOT RECRUITINGTargeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
ACTIVE NOT RECRUITINGOlaparib and Durvalumab (MEDI4736) in Patients with Metastatic Pancreatic Cancer and DNA Damage Repair Genes Alterations
ACTIVE NOT RECRUITINGFUnctional Selection of Advanced Breast Cancer Patients for Talazoparib Treatment Using the REpair Capacity (RECAP) Test
RECRUITINGStudy of LP-184 in Patients With Advanced Solid Tumors
RECRUITINGMEASUREMENT OF CIRCULATING MUTATION BURDEN
RECRUITINGTo Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.
ACTIVE NOT RECRUITINGProspective Study of MAstectomy With Reconstruction Including Robot Endoscopic Surgery
ACTIVE NOT RECRUITINGBRCA Mutation Carriers' Platform a Multicenter Study
RECRUITINGSerial Circulating Tumor DNA (ctDNA) Monitoring During Adjuvant Capecitabine in Early Triple-negative Breast Cancer
RECRUITINGExternal Resources
Links to major genomics databases and tools