BRCA1 and BRCA2 analysis of 268 HBOC and HBC families by DHPLC. T. Wagner¹, R. Moeslinger¹, D. Muhr¹, D. Richards³, M. Schreiber¹, E. Fleischmann¹, Austrian Hereditary Breast and Ovarian Cancer Group¹, G. Langbauer¹, C. Zielinski², L. Jin⁵, P. Oefner⁴. 1) Dept OB/GYN, Div Senology, Univ Vienna, Vienna, Austria; 2) Division of Oncology, Dep of Medicine!, University of Vienna; 3) Department of Genetics, Stanford University; 4) Stanford DNA Sequencing and Technology Center; 5) Human Genetics Center, University of Texas, Houston.
   Using denaturing high performance liquid chromatography and sequencing, the frequencies of BRCA1 and BRCA2 mutations in 268 Austrian families with hereditary breast cancer only (HBC) or breast and ovarian cancer (HBOC) were determined. In the BRCA1 gene 27 apparently disease-associated mutations were identified in 54 (20%) families. The percentage of disease-associated mutations was highest in the 60 HBOC families (40%), ranging from 23% in families with 1 BC and 1 OC to 80% with at least 3 BC and 2 OC. The overall frequency of BRCA1 mutations in the 193 HBC families was 14%, and as high as 50% in families with at least 4 BC <60 years. Nine founder mutations were detected that accounted for two thirds of all BRCA1 mutations. The two most frequently identified mutations were 1806CtoT (7 times) and 300TtoG (6 times). Additionally 10 unclassified variants were detected in the coding region of BRCA1. In the BRCA2 gene 10 apparently disease-associated mutations were identified in 17 (6%) families. One founder mutation accounted for 47% of all BRCA2 families in Austria. The percentage of disease-associated mutations was highest in families with male and female breast cancer (29%). In HBC families 5% could be explained by BRCA2 mutations, ranging from 7% in families with 3 BC cases to 25% with 4 BC < 60 years. In HBOC families only 8% BRCA2 mutations were detected. In the coding region of BRCA2 6 unclassified variants were detected. In conclusion 26% of families with HBC or HBOC can be explained by disease associated BRCA1 or BRCA2 mutations.