BRCA2
protein-codingBRCA2 DNA repair associated, the group of FA complementation groups
Gene summary
The product of this gene in involved in maintenance of genome stability. It is involved in double-strand break repair pathways during mitotic and meiotic homologous recombination and functions in protecting DNA replication forks. The encoded protein contains sites for interactions with PALB2 and EMSY and an N-terminal DNA binding domain. It also contains a RAD51 binding domain with multiple components. It has multiple BRC repeats, an alpha helix domain, oligonucleotide binding folds, and a tower-like domain. It has a nuclear localization signal and a phosphorylation site for cyclin-dependent kinase. The C-terminus of the protein can bind single-stranded and double-stranded DNA. The product of this gene interacts with multiple proteins, including RAD51. It is involved in recruiting RAD51 filaments to DNA double-strand break sites and also in cytoplasmic division. It also acts as a tumor suppressor. Mutations in this gene or decreased expression have been implicated in multiple tumor types, including breast, ovarian, pancreatic, prostate and other cancers. [provided by RefSeq, May 2026]
- FANCD1
- FACD
- FANCD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~85.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0011584
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0011584
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0011584
Submitter: ClinGen
There is abundant evidence published associating the BRCA2 gene with Fanconi anemia complementation group D1, since the gene-disease relationship was first proposed by Howlett et al. (2002). Multiple case level studies have been performed with FA patients that have variants in the BRCA2 gene. BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple Brca2 deficient mouse models have been established to show consistent phenotypes with FA patients including increased overall tumor incidence, decreased survival and hematopoietic dysfunction. Wildtype BRCA2 cDNA restored mitomycin C (MMC) resistance in patient derived fibroblasts. All of these types of evidence are consistent with a definitive relationship between the BRCA2 gene and Fanconi anemia complementation group D1.
Inheritance Pattern: AD
Disease ID:MONDO:0007959
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012933
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005089
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012933
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013235
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0700269
Submitter: ClinGen
BRCA2 plays a role as a tumor suppressor in transcriptional and cell cycle regulation, DNA double-strand breaks (DSBs) repair, mitophagy and stabilization of replication fork. In 1995, Wooster et al. (PMID: 8524414) identified BRCA2 gene and the association of breast cancer. Subsequently, the association of ovarian cancer and pancreatic cancer with germline BRCA2 variants was reported (PMID: 7597059, 9140390, 11257103). Emerging evidence also reported an increased risk of tumor formation at other sites including prostate 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 BRCA2-related cancer predisposition curation (MONDO:0700269). Association of germline pathogenic or likely pathogenic variants in the BRCA2 with autosomal recessive inherited Fanconi Anemia complementation group D1 (MONDO:0011584) has curated separately due to phenotypic variability and different inheritance patterns. The mechanism of pathogenicity is known to be loss-of-function. Three publications in which 6 founder variants from individuals and families with breast cancer and ovarian cancer (PMIDs: 8673092, 8673089 and 9361038) and 6 large case-control studies (PMID: 24728189, 28888541, 29922827, 30900310, 33471974, 33471991) are included in this curation. 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 (4.5 Points; PMIDs: 9126738, 9774970, 11694875, 15899802). Yeast two-hybrid assay showed that brca2 interacts with Rad51, a DNA-repair protein. Brca2-deficient mice were radiation sensitive. Mice with conditional mutants in Brca2 and/or p53 developed mammary tumors. In summary, BRCA2 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 as definitive for breast-ovarian cancer, familial, susceptibility to, 2 (MONDO:0012933) by the Breast/Ovarian Cancer GCEP on 09/13/2017. This re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 01/26/2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0019391
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0011584
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0012933
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0003582
Submitter: Orphanet
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 breast and ovarian 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; There are little empiric data regarding other cancer types, though awareness may allow early diagnosis and treatment; 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 BRCA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000059.4. 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 | 11 | 38 | 3637 | 41 | 3754 |
| missense | 197 | 154 | 4505 | 4917 | 221 | 9994 |
| nonsense | 1099 | 104 | 11 | 18 | 2 | 1234 |
| start loss | 6 | 2 | 1 | 9 | ||
| frameshift | 3804 | 380 | 52 | 39 | 4275 | |
| splice donor/acceptor (+/-2bp) | 138 | 168 | 30 | 1 | 1 | 338 |
| Total | 5271 | 819 | 4637 | 8612 | 265 | 19604 |
Highest pathogenic variant AF is 0.00013941574
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000050.3 | 26 | MANE Select | |
| Ensembl | ENSP00000369497.3 | 26 | MANE Select | |
| RefSeq | NP_001393648.1 | 25 | Standard | |
| RefSeq | NP_001393649.1 | 26 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| brca2 | Danio rerio | Structure: spermatocyte Quality: apoptotic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fanconi anemia pathway - Homo sapiens (human)
- Breast cancer - Homo sapiens (human)
- Homologous recombination - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Pancreatic cancer - Homo sapiens (human)
Biological Process
- mitotic cytokinesis
- telomere maintenance via recombination
- double-strand break repair via homologous recombination
- oocyte maturation
- inner cell mass cell proliferation
Molecular Function
- protease binding
- single-stranded DNA binding
- histone acetyltransferase activity
- protein binding
- protein C-terminus binding
Cellular Component
- nuclear chromosome, telomeric region
- lateral element
- nucleus
- nucleoplasm
- centrosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000544455
- Coding exons
- 26
- Length
- 84195
- Individuals with no LoFs
- 125654
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 94
- Defined
- 125748
- p
- 0.000374
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.29 | 1812 | 1.66e+3 | 1.09 | 0.0000806 | 22668 |
| Missense (PolyPhen) | 410 | 405.32 | 1.0116 | 6007 | ||
| Synonymous | 0.214 | 587 | 594 | 0.989 | 0.0000302 | 6253 |
| Loss of Function | 4.92 | 61 | 119 | 0.513 | 0.00000539 | 1807 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00076 | 0.00075 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00055 | 0.00055 | rare |
| European (Non-Finnish) | 0.00029 | 0.00029 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. Part of a PALB2-scaffolded HR complex containing RAD51C and which is thought to play a role in DNA repair by HR. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. May play a role in the extension step after strand invasion at replication-dependent DNA double-strand breaks; together with PALB2 is involved in both POLH localization at collapsed replication forks and DNA polymerization activity. In concert with NPM1, regulates centrosome duplication. Interacts with the TREX-2 complex (transcription and export complex 2) subunits PCID2 and SEM1, and is required to prevent R-loop- associated DNA damage and thus transcription-associated genomic instability. Silencing of BRCA2 promotes R-loop accumulation at actively transcribed genes in replicating and non-replicating cells, suggesting that BRCA2 mediates the control of R-loop associated genomic instability, independently of its known role in homologous recombination (PubMed:24896180). {ECO:0000269|PubMed:15115758, ECO:0000269|PubMed:15199141, ECO:0000269|PubMed:15671039, ECO:0000269|PubMed:18317453, ECO:0000269|PubMed:20729832, ECO:0000269|PubMed:20729858, ECO:0000269|PubMed:20729859, ECO:0000269|PubMed:21084279, ECO:0000269|PubMed:21719596, ECO:0000269|PubMed:24485656, ECO:0000269|PubMed:24896180}.;
- 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:10399947, ECO:0000269|PubMed:10978364, ECO:0000269|PubMed:11139248, ECO:0000269|PubMed:11241844, ECO:0000269|PubMed:11948477, ECO:0000269|PubMed:12145750, ECO:0000269|PubMed:12373604, ECO:0000269|PubMed:12442274, ECO:0000269|PubMed:12442275, ECO:0000269|PubMed:12938098, ECO:0000269|PubMed:14722926, ECO:0000269|PubMed:15026808, ECO:0000269|PubMed:15172753, ECO:0000269|PubMed:15365993, ECO:0000269|PubMed:16793542, ECO:0000269|PubMed:24013206, ECO:0000269|PubMed:8640237, ECO:0000269|PubMed:9150152, ECO:0000269|PubMed:9609997, ECO:0000269|PubMed:9654203, ECO:0000269|PubMed:9971877}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Pancreatic cancer 2 (PNCA2) [MIM:613347]: 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:9140390}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Breast-ovarian cancer, familial, 2 (BROVCA2) [MIM:612555]: 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. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Fanconi anemia complementation group D1 (FANCD1) [MIM:605724]: 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:12065746, ECO:0000269|PubMed:14670928, ECO:0000269|PubMed:16825431, ECO:0000269|PubMed:21719596}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glioma 3 (GLM3) [MIM:613029]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:15689453}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.703
Intolerance Scores
- LoFtool
- 0.0896
- RVIS EVS
- 3.73
- RVIS percentile EVS
- 99.59
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.854
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |