RAD51C
protein-codingRAD51 paralog C, the group of FA complementation groups
Gene summary
This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~43.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013253
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0013248
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0700273
Submitter: ClinGen
RAD51C is a member of the RAD51 gene family. The proteins of RAD51 family members are known to be involved in the homologous recombination and DNA repair. RAD51C protein can interact with other RAD51 paralogs and is reported to be involved in Holliday junction resolution. RAD51C has also been linked to autosomal recessive Fanconi anemia complementation group O. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split the autosomal recessive Fanconi anemia complementation group O into separate curations due to phenotypic variability and/or different inheritance patterns. Therefore, this curation solely focuses on autosomal dominant RAD51C-related cancer predisposition including familial ovarian cancer, triple negative breast cancer and ER negative breast cancers. This gene-disease relationship has been studied in at least eight case-control studies at the aggregate variant level . These case-control studies suggested significant increased risk for ovarian cancer, triple negative breast cancer and ER negative breast cancers in monoallelic RAD51C variant carriers compared to controls (12 points) (PMIDs: 26261251, 26720728, 30099541, 31341520, 32091585, 33471991, 35084436, 35172496). This gene-disease relationship is also supported by experimental evidence including expression and biomedical function studies (1.5 points; PMIDs: 20400963, 22167183, 23047548). The cells with loss of RAD51C or expressing RAD51C variants exhibited a marked increase in the frequency of interstrand cross-links and double strand breaks. Methylation of RAD51C promoter was also observed in the ovarian tumor samples. In summary, RAD51C is definitively associated with autosomal dominant RAD51C-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 familial ovarian cancer on 04/12/2017 and as disputed for hereditary breast carcinoma on 05/10/2017 by the Breast/Ovarian Cancer GCEP. This re-curation as definitive was approved by the ClinGen Hereditary Cancer GCEP on 03/22/2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0013248
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013248
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0003582
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0019391
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013248
Submitter: ClinGen
*RAD51C* is one of the more than twenty Fanconi anemia (FA) or FA-like genes known to cause autosomal recessive FA characterized by bone marrow failure, developmental abnormalities, and cancer predisposition. Biallelic variant in *RAD51C* was first identified in a patient with Fanconi anemia complementation group O (FANCO) in 2010 by Vaz et al. (PMID: 20400963). *RAD51C* is a member of the RAD51 gene family. The protein of RAD51 family members are known to be involved in the homologous recombination and repair of DNA. RAD51C protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Monoallelic *RAD51C* variants were also linked to autosomal dominant familial ovarian cancer and triple negative breast cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split autosomal dominant triple negative breast cancer and ovarian cancer into separate curations due to phenotypic variability and different inheritance patterns. Therefore, this curation solely focuses on autosomal recessive FANCO. Three variants (1 intronic variant predicted to result in splice effect and 2 missense variants) identified in 2 families are included in this curation (2.6 points; PMIDs: 20400963, 29278735). The mechanism of pathogenicity appears to be loss of function (LOF). This gene-disease relationship is also supported by experimental evidence including animal models and biomedical function studies (2.5 points; PMIDs: 22167183, 30540754, 36906610). The cells with loss of *RAD51C* or expressing *RAD51C* variants exhibited a marked increase in the frequency of interstrand cross-links and double strand breaks. Knockout zebrafish model exhibited a partial female sex reversal. This reversal may illustrate that the *RAD51C* gene is important for gonadogenesis and may reflect the commonly observed hypogonadism in FA probands. Mice with double knockout of Rad51c and Brca2 demonstrates phenotypes seen in FA patients including DNA replication instability, higher spontaneous chromosomal aberrations, bone marrow failure, leukemia, reduced survivability. Combination of genetic and experimental evidence has not demonstrated convincing definitive validity of *RAD51C* gene in inherited FANCO. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the role of *RAD51C* in FANCO. This gene-disease pair was originally evaluated as moderate by the General Gene Curation GCEP on 1/5/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 07/28/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0013253
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013248
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013253
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Oncologic; Renal
Intervention: Allergy/Immunology/Infectious; Cardiovascular; Hematologic; Oncologic
Rationale: In Breast-ovarian cancer susceptibility, surveillance (similar to that indicated in individuals with BRCA1 or BRCA2 variants) may allow early detection and treatment of tumors, which may reduce morbidity and mortality; For Fanconi anemia, specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count); 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to RAD51C variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_058216.3. 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 | 1 | 2 | 8 | 355 | 41 | 407 |
| missense | 8 | 64 | 694 | 281 | 41 | 1088 |
| nonsense | 48 | 25 | 1 | 74 | ||
| start loss | 1 | 7 | 8 | |||
| frameshift | 117 | 60 | 9 | 186 | ||
| splice donor/acceptor (+/-2bp) | 6 | 63 | 7 | 76 | ||
| Total | 181 | 214 | 726 | 636 | 82 | 1839 |
Highest pathogenic variant AF is 0.00004590607
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_478123.1 | 9 | MANE Select | |
| Ensembl | ENSP00000336701.4 | 9 | MANE Select | |
| RefSeq | NP_002867.1 | 2 | Standard | |
| Ensembl | ENSP00000401741.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Fanconi anemia pathway - Homo sapiens (human)
- Homologous recombination - Homo sapiens (human)
- HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)
- DNA Repair
- DNA Double-Strand Break Repair
Biological Process
- telomere maintenance via recombination
- double-strand break repair via homologous recombination
- DNA repair
- DNA recombination
- sister chromatid cohesion
Molecular Function
- four-way junction DNA binding
- DNA binding
- protein binding
- ATP binding
- DNA-dependent ATPase activity
Cellular Component
- nucleus
- nucleoplasm
- replication fork
- cytoplasm
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000337432
- Coding exons
- 9
- Length
- 41770
- Individuals with no LoFs
- 125632
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 116
- Defined
- 125748
- p
- 0.000461
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.126 | 200 | 205 | 0.975 | 0.0000104 | 2419 |
| Missense (PolyPhen) | 45 | 50.51 | 0.89092 | 533 | ||
| Synonymous | 0.184 | 69 | 71.0 | 0.972 | 0.00000310 | 750 |
| Loss of Function | -0.110 | 20 | 19.5 | 1.03 | 0.00000106 | 230 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00082 | 0.00082 | rare |
| Finnish | 0.00042 | 0.00042 | rare |
| European (Non-Finnish) | 0.00048 | 0.00047 | rare |
| South Asian | 0.00082 | 0.00082 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Essential for the homologous recombination (HR) pathway of DNA repair. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Part of the RAD21 paralog protein complexes BCDX2 and CX3 which act at different stages of the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 seems to act downstream of BRCA2 recruitment and upstream of RAD51 recruitment; CX3 seems to act downstream of RAD51 recruitment; both complexes bind predominantly to the intersection of the four duplex arms of the Holliday junction (HJ) and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. The BCDX2 subcomplex RAD51B:RAD51C exhibits single-stranded DNA-dependent ATPase activity suggesting an involvement in early stages of the HR pathway. Involved in RAD51 foci formation in response to DNA damage suggesting an involvement in early stages of HR probably in the invasion step. Has an early function in DNA repair in facilitating phosphorylation of the checkpoint kinase CHEK2 and thereby transduction of the damage signal, leading to cell cycle arrest and HR activation. Participates in branch migration and HJ resolution and thus is important for processing HR intermediates late in the DNA repair process; the function may be linked to the CX3 complex. Part of a PALB2-scaffolded HR complex containing BRCA2 and which is thought to play a role in DNA repair by HR. Protects RAD51 from ubiquitin-mediated degradation that is enhanced following DNA damage. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51 and XRCC3. Contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Involved in maintaining centrosome number in mitosis. {ECO:0000269|PubMed:14716019, ECO:0000269|PubMed:16215984, ECO:0000269|PubMed:16395335, ECO:0000269|PubMed:19451272, ECO:0000269|PubMed:19783859, ECO:0000269|PubMed:20413593, ECO:0000269|PubMed:23108668, ECO:0000269|PubMed:23149936}.;
- Disease
- DISEASE: Fanconi anemia complementation group O (FANCO) [MIM:613390]: 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:20400963, ECO:0000269|PubMed:24141787}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Breast-ovarian cancer, familial, 3 (BROVCA3) [MIM:613399]: 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:20400964, ECO:0000269|PubMed:21990120, ECO:0000269|PubMed:24141787}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.166
Intolerance Scores
- LoFtool
- 0.704
- RVIS EVS
- 0.11
- RVIS percentile EVS
- 61.73
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.972
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |