Screening of 1331 Danish breast and/or ovarian cancer families identified 40 novel BRCA1 and BRCA2 mutations Thomas v. O. Hansen • Lars Jønson • Ane Y. Steffensen • Mette K. Andersen • Susanne Kjaergaard • Anne-Marie Gerdes • Bent Ejlertsen • Finn C. Nielsen Published online: 12 February 2011 Ó Springer Science+Business Media B.V. 2011 Abstract Germ-line mutations in the tumour suppressor genes BRCA1 and BRCA2 predispose to breast and ovarian cancer. Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. During this period we have identified 40 novel sequence variations in BRCA1 and BRCA2 in high risk breast and/or ovarian cancer families. The mutations were detected via pre-screening using dHPLC or high-resolution melting and direct sequencing. We identified 16 variants in BRCA1, including 9 deleterious frame-shift mutations, 2 intronic variants, 4 missense mutations, and 1 synonymous variant. The remaining 24 variants were identified in BRCA2, including 10 deleterious mutants (6 frame-shift and 4 non- sense), 2 intronic variants, 10 missense mutations and 2 synonymous variants. The frequency of the variants of unknown significance was examined in control individuals. Moreover, the presumed significance of the missense mutations was predicted in silico using the align GVGD algorithm. In conclusion, the mutation screening identified 40 novel variants in the BRCA1 and BRCA2 genes and thereby extends the knowledge of the BRCA1/BRCA2 mutation spectrum. Nineteen of the mutations were inter- preted as pathogenic, 3 missense mutations were suggested to be pathogenic based on in silico analysis, 6 mutations were suggested to be benign since they were identified in patients together with a well-known disease-causing BRCA1/BRCA2 mutation, while 12 were variants of unknown significance. Keywords BRCA1 Á BRCA2 Á Breast cancer Á East Denmark Á Mutation Á Novel Á Ovarian cancer Introduction Breast cancer is the most common cancer among women with a lifetime risk around 10%. BRCA1 (MIM 113705) and BRCA2 (MIM 600185) germ-line mutations confer high risks of breast and ovarian cancer. The breast cancer risks for BRCA1 and BRCA2 mutation carriers have been estimated to 40–87% by age 70, while the risk for ovarian cancer have been estimated to 11–39% by age 70 [1, 2]. Mutations in BRCA1 and BRCA2 are scattered throughout both genes (listed in Breast Cancer Information Core (BIC)— http://www.research.nhgri.nih.gov/bic/), and include disease- causing mutations such as large genomic rearrangements, frame-shift, nonsense, and splicing mutations, of which sev- eral have been identified in Danish breast and/or ovarian cancer families [3–8]. Several founder mutations have been identified in a variety of different populations, including Ashkenazi Jews, Icelanders and Greenlandic Inuit’s [9–11]. Moreover a high proportion of missense, silence and intron variants are reported. These variants are often classified as variants of unknown significance (VUS). Since 1999 we have performed mutational screening of breast and/or ovarian cancer patients in East Denmark. T. v. O. Hansen (&) Á L. Jønson Á A. Y. Steffensen Á F. C. Nielsen Genomic Medicine, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark e-mail: tvoh@rh.dk M. K. Andersen Á S. Kjaergaard Á A.-M. Gerdes Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark B. Ejlertsen Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark 123 Familial Cancer (2011) 10:207–212 DOI 10.1007/s10689-011-9422-5