MODERATE FREQUENCY OF BRCA1 AND BRCA2 GERM-LINE MUTATIONS IN SCANDINAVIAN FAMILIAL BREAST-CANCER

Previous studies of high-risk breast cancer families have proposed tha t two major breast cancer-susceptibility genes, BRCA1 and BRCA2, may a ccount for at least two-thirds of all hereditary breast cancer. We hav e screened index cases from 106 Scandinavian (mainly southern Swedish) breast cancer and breast-ovarian cancer families for germ-line mutati ons in all coding exons of the BRCA1, and BRCA2 genes, using the prote in-truncation test, SSCP analysis, or direct sequencing. A total of 24 families exhibited 11 different BRCA1 mutations, whereas 11 different BRCA2 mutations were detected in 12 families, of which 3 contained ca ses of male breast cancer. One BRCA2 mutation, 4486delG, was found in two families of the present study and, in a separate study, also in br east tumors from three unrelated males with unknown family history, su ggesting that at least one BRCA2 founder mutation exists in the Scandi navian population. We report 1 novel BRCA1 mutation, eight additional cases of 4 BRCA1 mutations described elsewhere, and 11 novel BRCA2 mut ations (3 frameshift deletions and 2 nonsense mutations), of which all are predicted to cause premature truncation of the translated product s. The relatively low frequency of BRCA1 and BRCA2 mutations in the pr esent study could be explained by insufficient screening sensitivity t o the location of mutations in uncharacterized regulatory regions, the analysis of phenocopies, or, most likely, within predisposed families , additional uncharacterized BRCA genes.