Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene
Abstract
Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.
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CHEK2, ATM, NBS1, RAD50, TOPBP1, and RAD51C are mutated in breast cancer patients.
“Correspondingly, these and other genes functioning in the DNA damage response, such as CHEK2, ATM, NBS1, RAD50, TOPBP1 and RAD51C, are mutated in breast cancer patients [12–21].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [21]
RAD51C mutations occur in breast cancer and in a consanguineous family with severe congenital abnormalities characteristic of Fanconi anemia.
“Conceivably, RAD51C will also join the BRCA-FA family given that mutations were found not only in breast cancer [21], but also in a consanguineous family with severe congenital abnormalities characteristic of FA [31].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [21]
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“In addition, the high penetrance of mutations impairing RAD51C function, and the causative link with the occurrence of gynecological cancers, justifies testing of other malignancie”
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- Authors
- Meindl, A., Hellebrand, H., Wiek, C., Erven, V., Wappenschmidt, B., Niederacher, D., Freund, M., Lichtner, P., Hartmann, L., Schaal, H., Ramser, J., Honisch, E., Kubisch, C., Wichmann, H. E., Kast, K., Deißler, H., Engel, C., Müller-Myhsok, B., Neveling, K., Kiechle, M., Mathew, C. G., Schindler, D., Schmutzler, R. K., & Hanenberg, H.
- Affiliations
- TUM Klinikum (DE)
- Heinrich Heine University Düsseldorf (DE)
- University Hospital Cologne (DE)
- Helmholtz Munich (DE)
- University of Cologne (DE)
- University Hospital Carl Gustav Carus (DE)
- Universität Ulm (DE)
- Leipzig University (DE)
- University of Würzburg (DE)
- Guy's Hospital (GB)
- Riley Hospital for Children (US)
- Corresponding author
- Meindl, Alfons
- Hanenberg, Helmut
- ORCID
- Venue
- Nature Genetics
- Published
- 2010-04-18
- Volume
- 42
- Issue
- 5
- Pages
- 410-414
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2041205258
- Cited by
- 743
- References
- 35
- Citations by year
- 2026: 20 · 2025: 19 · 2024: 23 · 2023: 26 · 2022: 31 · 2021: 33 · 2020: 40 · 2019: 37 · 2018: 46 · 2017: 54 · 2016: 69 · 2015: 60 · 2014: 59 · 2013: 66 · 2012: 71
- FWCI
- 40.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- RAD51C, germline mutations, breast cancer, ovarian cancer, cancer susceptibility genes, hereditary cancer predisposition, homologous recombination repair, DNA double-strand break repair, pedigree analysis, missense mutations, splice site mutation, frameshift insertion
- MeSH terms
- Alleles, Breast Neoplasms, DNA-Binding Proteins, Fanconi Anemia, Female, Germany, Humans, Models, Genetic, Mutation, Ovarian Neoplasms, Pedigree, Phenotype, Case-Control Studies, Germ-Line Mutation, Genetic Predisposition to Disease
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