A HIGH PROPORTION OF MUTATIONS IN THE BRCA1 GENE IN GERMAN BREAST OVARIAN CANCER FAMILIES WITH CLUSTERING OF MUTATIONS IN THE 3'-3RD OF THEGENE/

We have analyzed 61 German breast and breast/ovarian cancer families f or BRCA1 mutations using single-strand conformation polymorphism analy sis (SSCP) followed by sequencing. Forty-seven of the families had at least three cases (at least two under 60 years) and 14 families had on ly two cases of breast/ovarian cancer (at least one under 50 years). T wenty-eight families were breast/ovarian and 33 were breast cancer-onl y families. Eighteen mutations in BRCA1 were detected in 11/28 breast/ ovarian cancer families and 7/33 breast cancer families and none in th e families with only two cases. We identified 17 truncation mutations (8 frameshift, 7 nonsense and 2 splice variants) and one missense muta tion. Seven of these are novel and two, the 5382insC and 5622C --> T m utations, occurred in two apparently unrelated families. The genotype of the two families with the 5382insC mutation is compatible with the rare haplotype segregating with the 5382insC mutation in different pop ulations, further supporting its European origin. One unclassified mis sense alteration, R841W, was found in one family but did not segregate with the disease, suggesting that it is more likely a polymorphism. W e also report and discuss the sequence of several new unclassified sin gle-nucleotide changes first identified by SSCP, Of the 18 mutations, 13 occurred in the 3' third of the gene (end of exon 11-24) and ovaria n cancers were found in eight of these families.