Abstract
Next-generation sequencing has entered routine genetic testing of hereditary breast cancer. It has provided the opportunity to screen multiple genes simultaneously, and consequently has identified new complex genotypes. Here we report the first identification of a woman double heterozygote for mutations in the RAD51C and BRCA2 genes. The RAD51C missense mutation p.Arg258His has previously been identified in a homozygous state in a patient with Fanconi anemia. This mutation is known to affect the DNA repair function of the RAD51C protein. The BRCA2 p.Leu3216Leu synonymous mutation has not been described before and mini-gene splicing experiments revealed that the mutation results in skipping of exon 26 containing a part of the DNA-binding domain. We conclude that the woman has two potential disease-causing mutations and that predictive testing of family members should include both the RAD51C and BRCA2 mutation. This study illustrates the advantage of sequencing gene panels using next-generation sequencing in terms of genetic testing.
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References
King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646. doi:10.1126/science.1088759
van der Groep P, van der Wall E, van Diest PJ (2011) Pathology of hereditary breast cancer. Cell Oncol (Dordr) 34(2):71–88. doi:10.1007/s13402-011-0010-3
Godthelp BC, Wiegant WW, van Duijn-Goedhart A et al (2002) Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Nucleic Acids Res 30(10):2172–2182
Liu Y, Tarsounas M, O’Regan P, West SC (2007) Role of RAD51C and XRCC3 in genetic recombination and DNA repair. J Biol Chem 282(3):1973–1979
Vaz F, Hanenberg H, Schuster B et al (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409
Kushnir A, Laitman Y, Shimon SP, Berger R, Friedman E (2012) Germline mutations in RAD51C in Jewish high cancer risk families. Breast Cancer Res Treat 136(3): 869–874. doi:10.1007/s10549-012-2317-9
Meindl A, Hellebrand H, Wiek C, et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414
Osorio A, Endt D, Fernandez F et al (2012) Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Hum Mol Genet 21(13):2889–2898
Kee Y, D’Andrea AD (2012) Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest 122(11):3799–3806
Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A (2008) Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum Mutat 29(11):1342–1354. doi:10.1002/humu.20896
Thery JC, Krieger S, Gaildrat P et al (2011) Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet 19(10):1052–1058
Steffensen AY, Dandanell M, Jonson L et al (2014) Functional characterization of BRCA1 gene variants by mini-gene splicing assay. Eur J Hum Genet. doi:10.1038/ejhg.2014.40
Cruger DG, Kruse TA, Gerdes AM (2005) ‘Indirect’ BRCA1/2 testing: a useful approach in hereditary breast and ovarian cancer families without a living affected relative. Clin Genet 68(3):228–233
Vreeswijk MP, Kraan JN, van der Klift HM et al (2009) Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 30(1):107–114. doi:10.1002/humu.20811
Leegte B, van der Hout AH, Deffenbaugh AM et al (2005) Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet 42(3):e20
Caldes T, de la Hoya M, Tosar A et al (2002) A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes. J Med Genet 39(8):e44
Choi DH, Lee MH, Bale AE, Carter D, Haffty BG (2004) Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol 22(9):1638–1645. doi:10.1200/JCO.2004.04.179
Smith M, Fawcett S, Sigalas E et al (2008) Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes. Fam Cancer 7(2):119–124. doi:10.1007/s10689-007-9154-8
Steffensen AY, Jonson L, Ejlertsen B, Gerdes AM, Nielsen FC, Hansen TV (2010) Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations. Fam Cancer 9(3): 283–287. doi:10.1007/s10689-010-9345-6
Rainville IR, Rana HQ (2014) Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. Curr Oncol Rep 16(3):371. doi:10.1007/s11912-013-0371-z
Park JY, Singh TR, Nassar N et al (2013) Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene. doi:10.1038/onc.2013.421
Alamut version 2.2 (Interactive Biosoftware, Rouen, France)
French CA, Tambini CE, Thacker J (2003) Identification of functional domains in the RAD51L2 (RAD51C) protein and its requirement for gene conversion. J Biol Chem 278(46):45445–45450. doi:10.1074/jbc.M308621200
Yang H, Jeffrey PD, Miller J et al (2002) BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297(5588):1837–1848. doi:10.1126/science.297.5588.1837
Guidugli L, Pankratz VS, Singh N et al (2013) A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res 73(1):265–275
Szabo C, Masiello A, Ryan JF, Brody LC (2000) The breast cancer information core: database design, structure, and scope. Hum Mutat 16(2):123–131. doi:10.1002/1098-1004(200008)16:2<123:AID-HUMU4>3.0.CO;2-Y
Acknowledgments
We thank Stine Østergaard for technical assistance. This study was supported by the Familien Hede Nielsens Foundation.
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Ahlborn, L.B., Steffensen, A.Y., Jønson, L. et al. Identification of a breast cancer family double heterozygote for RAD51C and BRCA2 gene mutations. Familial Cancer 14, 129–133 (2015). https://doi.org/10.1007/s10689-014-9747-y
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DOI: https://doi.org/10.1007/s10689-014-9747-y