BRCA1
protein-codingBRCA1 DNA repair associated, the group of Ring finger proteins|FA complementation groups|BRCA1 B complex|BRCA1 C complex|BRCA1 A complex|Protein phosphatase 1 regulatory subunits
Gene summary
This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~126.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0019391
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011450
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0003582
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0054748
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013685
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0054748
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011450
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0700268
Submitter: ClinGen
The BRCA1 protein plays a role as a tumor suppressor, functioning in different cellular processes, including DNA double-strand breaks (DSBs) repair, transcriptional activation, cell cycle regulation and chromatin remodeling. In 1994, Miki et al. identified BRCA1 gene and the association of breast cancer and ovarian cancer. In 2008, Al-Sukhni et al. further found germline BRCA1 variants are linked to pancreatic cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or inheritance pattern. Therefore, these phenotypes have been lumped into this BRCA1-related cancer predisposition curation. Please note that association of germline pathogenic or likely pathogenic variants in the BRCA1 with autosomal recessive inherited Fanconi Anemia complementation group S (MONDO:0054748) has been split to another curation due to phenotypic variability and different inheritance patterns. 6 families in the Miki et al (PMID: 7545954) and 4 large case-control studies (PMIDs: 12237281, 29922827, 34471974, 34471991) are included in this curation. The mechanism of pathogenicity is known to be loss-of-function. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence (5.5 points; PMIDs: 7795653, 8589721, 10198641, 10549283, 11562181). A defective G2-M checkpoint accompanied by extensive chromosomal abnormalities was observed in BRCA1 mutant cells. Overexpression of BRCA1 in breast and ovarian cancer cell lines inhibited cell growth. Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DSBs by homologous recombination. Additionally, The Brca1 conditional knockout mice developed mammary tumors with massive chromosomal abnormalities. In summary, BRCA1 is definitively associated with autosomal dominant BRCA2-related cancer predisposition. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated for breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450) as definitive by the Breast/Ovarian Cancer GCEP on 09/13/2017. This re-curation as Definitive was approved by the ClinGen Hereditary Cancer GCEP on 08/25/2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0054748
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011450
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0054748
Submitter: ClinGen
Fanconi anemia complementation group S (FANCS, OMIM:617883) is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Homozygous or compound heterozygous pathogenic variants in BRCA1 have been reported to be associated with FANCS. In total, eight affected individuals with FANCS from six unrelated families were curated here. All three adult probands have breast or ovarian cancer diagnosed before age of 30 (PMID: 23269703; 25472942; 31347298). Two out of five younger probands were diagnosed with cancer: one with T-cell acute lymphoblastic leukemia at age 5 and one with neuroblastoma at age 2 (PMID:29712865). BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple reports of functional assays using patients cells have consistent/similar results. For example, Sawyer SL, et al., 2015 (PMID: 25472942) indicated patient primary skin fibroblast cells showed reduced BRCA1 and Rad51 foci formation at IR induced damage sites and exhibited deficiency in DSB recognition. Rescue studies of PARP inhibition by Olaparib were also reported. In summary, BRCA1 is definitively associated with the autosomal recessive FANCS disorder. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Craniofacial; Dermatologic; Hematologic; Musculoskeletal; Neurologic; Oncologic
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic
Rationale: For hereditary cancer, though the availability of empirical data is incomplete as applies to both screening strategies and prophylactic treatment, surveillance is based on the age of affected family members (for breast cancer, surveillance includes self-examination as well as regular clinical examinations, mammography, and MRI; for ovarian cancer, screening includes regular pelvic examination, transvaginal ultrasounds with Doppler, and CA-125 measurement; for prostate cancer, screening includes regular rectal examination and PSA measurement); Prophylactic mastectomy and/or oophorectomy, as well as chemoprevention (eg, with tamoxifen) are described; Treatment of breast and ovarian cancer follows standard guidelines (ie, that apply more generally), though, new targeted therapies are under investigation; For individuals with metastatic Prostate cancer, management with PARP-inhibitors has been described as improving progression-free survival; For Fanconi anemia: specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count), and HSCT can be curative, but solid tumor risk may remain; Surveillance for complications such as bone marrow failure is recommended; Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management
Comments: Variants may also predispose to a number of other malignancies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BRCA1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_007294.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 27 | 7 | 305 | 1711 | 25 | 2075 |
| missense | 173 | 221 | 3454 | 2484 | 166 | 6498 |
| nonsense | 658 | 35 | 50 | 2 | 745 | |
| start loss | 6 | 2 | 2 | 10 | ||
| frameshift | 2713 | 190 | 50 | 2953 | ||
| splice donor/acceptor (+/-2bp) | 226 | 99 | 90 | 1 | 1 | 417 |
| Total | 3803 | 554 | 3951 | 4198 | 192 | 12698 |
Highest pathogenic variant AF is 0.00011848018
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_009225.1 | 22 | MANE Select | |
| Ensembl | ENSP00000350283.3 | 22 | MANE Select | |
| RefSeq | NP_001394500.1 | 20 | Standard | |
| RefSeq | NP_001394510.1 | 23 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- PI3K-Akt signaling pathway - Homo sapiens (human)
- Fanconi anemia pathway - Homo sapiens (human)
- Ubiquitin mediated proteolysis - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Homologous recombination - Homo sapiens (human)
Biological Process
- double-strand break repair via homologous recombination
- DNA double-strand break processing
- DNA replication
- postreplication repair
- double-strand break repair
Molecular Function
- DNA binding
- damaged DNA binding
- transcription coactivator activity
- RNA binding
- ubiquitin-protein transferase activity
Cellular Component
- ubiquitin ligase complex
- lateral element
- nucleus
- nucleoplasm
- chromosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000471181
- Coding exons
- 23
- Length
- 81189
- Individuals with no LoFs
- 125577
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 171
- Defined
- 125748
- p
- 0.000680
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.582 | 891 | 941 | 0.947 | 0.0000462 | 12573 |
| Missense (PolyPhen) | 150 | 179.14 | 0.83732 | 2772 | ||
| Synonymous | 0.511 | 329 | 341 | 0.965 | 0.0000173 | 3439 |
| Loss of Function | 2.16 | 55 | 75.2 | 0.731 | 0.00000358 | 1052 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000069 | 0.000062 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.0064 | 0.0065 | notable |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00063 | 0.00062 | rare |
| South Asian | 0.00042 | 0.00042 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator (PubMed:20160719). {ECO:0000269|PubMed:10500182, ECO:0000269|PubMed:10724175, ECO:0000269|PubMed:11836499, ECO:0000269|PubMed:12887909, ECO:0000269|PubMed:12890688, ECO:0000269|PubMed:14976165, ECO:0000269|PubMed:14990569, ECO:0000269|PubMed:16326698, ECO:0000269|PubMed:16818604, ECO:0000269|PubMed:17525340, ECO:0000269|PubMed:18056443, ECO:0000269|PubMed:19261748, ECO:0000269|PubMed:19369211, ECO:0000269|PubMed:20160719, ECO:0000269|PubMed:20351172, ECO:0000269|PubMed:20364141}.;
- Disease
- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. {ECO:0000269|PubMed:10323242, ECO:0000269|PubMed:11114888, ECO:0000269|PubMed:11301010, ECO:0000269|PubMed:12427738, ECO:0000269|PubMed:12442275, ECO:0000269|PubMed:12938098, ECO:0000269|PubMed:14722926, ECO:0000269|PubMed:15133502, ECO:0000269|PubMed:18285836, ECO:0000269|PubMed:21473589, ECO:0000269|PubMed:23867111, ECO:0000269|PubMed:28364669, ECO:0000269|PubMed:7545954, ECO:0000269|PubMed:7894491, ECO:0000269|PubMed:7894493, ECO:0000269|PubMed:7939630, ECO:0000269|PubMed:8554067, ECO:0000269|PubMed:8723683, ECO:0000269|PubMed:8776600, ECO:0000269|PubMed:9482581, ECO:0000269|PubMed:9609997, ECO:0000269|PubMed:9760198}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for 45% of inherited breast cancer. Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3-fold increased risk of prostate cancer. Cells lacking BRCA1 show defects in DNA repair by homologous recombination.; DISEASE: Breast-ovarian cancer, familial, 1 (BROVCA1) [MIM:604370]: A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. {ECO:0000269|PubMed:12938098, ECO:0000269|PubMed:14722926, ECO:0000269|PubMed:28364669, ECO:0000269|PubMed:8968716}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Mutations in BRCA1 are thought to be responsible for more than 80% of inherited breast-ovarian cancer.; DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:10196379, ECO:0000269|PubMed:10486320, ECO:0000269|PubMed:14746861, ECO:0000269|PubMed:28364669}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Pancreatic cancer 4 (PNCA4) [MIM:614320]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. {ECO:0000269|PubMed:18762988}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Fanconi anemia, complementation group S (FANCS) [MIM:617883]: A form of Fanconi anemia, a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. {ECO:0000269|PubMed:23269703, ECO:0000269|PubMed:25472942, ECO:0000269|PubMed:29133208}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.948
Intolerance Scores
- LoFtool
- 0.00207
- RVIS EVS
- 0.46
- RVIS percentile EVS
- 78.6
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | High | Medium | High |