Familial Cancer

, Volume 14, Issue 1, pp 129–133 | Cite as

Identification of a breast cancer family double heterozygote for RAD51C and BRCA2 gene mutations

  • Lise B. Ahlborn
  • Ane Y. Steffensen
  • Lars Jønson
  • Malene Djursby
  • Finn C. Nielsen
  • Anne-Marie Gerdes
  • Thomas V. O. Hansen
Original Article
First Online:

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.

Keywords

BRCA2 RAD51C Breast cancer Double heterozygote Mutation Next-generation sequencing 
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Notes

Acknowledgments

We thank Stine Østergaard for technical assistance. This study was supported by the Familien Hede Nielsens Foundation.

References

  1. 1.
    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 CrossRefPubMedGoogle Scholar
  2. 2.
    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
  3. 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):2172–2182CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    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):1973–1979CrossRefPubMedGoogle Scholar
  5. 5.
    Vaz F, Hanenberg H, Schuster B et al (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409Google Scholar
  6. 6.
    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
  7. 7.
    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):410–414Google Scholar
  8. 8.
    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):2889–2898Google Scholar
  9. 9.
    Kee Y, D’Andrea AD (2012) Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest 122(11):3799–3806Google Scholar
  10. 10.
    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 CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    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):1052–1058Google Scholar
  12. 12.
    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
  13. 13.
    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):228–233CrossRefPubMedGoogle Scholar
  14. 14.
    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 CrossRefPubMedGoogle Scholar
  15. 15.
    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):e20CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    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):e44CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    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 CrossRefPubMedGoogle Scholar
  18. 18.
    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 CrossRefPubMedGoogle Scholar
  19. 19.
    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
  20. 20.
    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
  21. 21.
    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
  22. 22.
    Alamut version 2.2 (Interactive Biosoftware, Rouen, France)Google Scholar
  23. 23.
    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 CrossRefPubMedGoogle Scholar
  24. 24.
    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 CrossRefPubMedGoogle Scholar
  25. 25.
    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):265–275Google Scholar
  26. 26.
    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 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Lise B. Ahlborn
    • 1
  • Ane Y. Steffensen
    • 1
  • Lars Jønson
    • 1
  • Malene Djursby
    • 2
  • Finn C. Nielsen
    • 1
  • Anne-Marie Gerdes
    • 2
  • Thomas V. O. Hansen
    • 1
  1. 1.Center for Genomic MedicineRigshospitalet, University of CopenhagenCopenhagenDenmark
  2. 2.Department of Clinical GeneticsRigshospitalet, University of CopenhagenCopenhagenDenmark

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