Abstract
Germ-line mutations in BRCA2 predispose to breast and ovarian cancer. Mutations are widespread throughout the gene and include disease-causing mutations as frameshift, nonsense, splicing mutations and large genomic rearrangements. However a large number of mutations, including missense, silent and intron variants are of unknown significance. Here, we describe the functional characterization of a silent mutation (nucleotide 744 G → A/c.516 G → A, Lys172Lys) in exon 6 of BRCA2 in a Danish family with breast and ovarian cancer. Exon trapping analysis showed that the mutation results in skipping of exon 6 and/or both exon 5 and 6, which was verified by RT-PCR analysis on RNA isolated from whole blood of the affected patient. We therefore conclude that the BRCA2 silent mutation Lys172Lys is a disease-causing mutation.
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Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. doi:10.1086/375033
Gudmundsdottir K, Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25(43):5864–5874. doi:10.1038/sj.onc.1209874
Hansen TVO, Jonson L, Albrechtsen A, Andersen MK, Ejlertsen B, Nielsen FC (2008) Large BRCA1 and BRCA2 genomic rearrangements in Danish high risk breast-ovarian cancer families. Breast Cancer Res Treat 12. doi:10.1007/s10549-008-0088-0
Thomassen M, Hansen TV, Borg A, Lianee HT, Wikman F, Pedersen IS, Bisgaard ML, Nielsen FC, Kruse TA, Gerdes AM (2008) BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol 47(4):772–777. doi:10.1080/02841860802004974
Hansen TVO, Ejlertsen B, Albrechtsen A, Bergsten E, Bjerregaard P, Hansen T, Myrhoj T, Nielsen PB, Timmermans-Wielenga V, Andersen MK, et al (2008) A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat 26. doi:10.1007/s10549-008-0060-z
Hansen TV, Bisgaard ML, Jonson L, Albrechtsen A, Filtenborg-Barnkob B, Eiberg H, Ejlertsen B, Nielsen FC (2008) Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 9:58. doi:10.1186/1471-2350-9-58
Vreeswijk MP, Kraan JN, van der Klift HM, Vink GR, Cornelisse CJ, Wijnen JT, Bakker E, van Asperen CJ, Devilee P (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
Church DM, Stotler CJ, Rutter JL, Murrell JR, Trofatter JA, Buckler AJ (1994) Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nat Genet 6(1):98–105. doi:10.1038/ng0194-98
Wang Z, Burge CB (2008) Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA 14(5):802–813. doi:10.1261/rna.876308
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3(4):285–298. doi:10.1038/nrg775
Maillet P, Chappuis PO, Khoshbeen-Boudal M, Sciretta V, Sappino AP (2006) Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families. Cancer Genet Cytogenet 169(1):62–68. doi:10.1016/j.cancergencyto.2006.03.010
Claes K, Poppe B, Machackova E, Coene I, Foretova L, De Paepe A, Messiaen L (2003) Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2. Genes Chromosomes Cancer 37(3):314–320. doi:10.1002/gcc.10221
Perrin-Vidoz L, Sinilnikova OM, Stoppa-Lyonnet D, Lenoir GM, Mazoyer S (2002) The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum Mol Genet 11(23):2805–2814. doi:10.1093/hmg/11.23.2805
Ware MD, DeSilva D, Sinilnikova OM, Stoppa-Lyonnet D, Tavtigian SV, Mazoyer S (2006) Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene? Oncogene 25(2):323–328
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This study was supported by the Neye Foundation and the Danish Cancer Society.
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Hansen, T.V.O., Steffensen, A.Y., Jønson, L. et al. The silent mutation nucleotide 744 G → A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping. Breast Cancer Res Treat 119, 547–550 (2010). https://doi.org/10.1007/s10549-009-0359-4
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DOI: https://doi.org/10.1007/s10549-009-0359-4