Women harboring BRCA1 germline mutations carry an 85% lifetime risk of developing breast cancer and a 63% risk of ovarian cancer. In this first systematic study of familial breast and/or ovarian cancer in Germany we investigated 29 families for germline mutations in the BRCA1 gene. We identified mutations in three breast cancer families and in four breast-ovarian cancer families. The mutations include one missense mutation, one frameshift mutation, one splice mutation, and four nonsense mutations cosegregating with breast and/or ovarian susceptibility in five of ten (50%) families showing positive evidence of linkage to chromosome band 17q21 and in two of 19 (11%) families where linkage data was not available. Two apparently unrelated families carried the same nonsense mutation at codon 1835 and three families harbored a C to T transition at nucleotide 49 of the untranslated exon 4. Allelotyping of the markers D17S855, D17S1322, D17S1323, and D17S1327 located within or near BRCA1 revealed that all affected individuals in the two families harboring the mutation at codon 1835 shared at least one allele indicating a founder mutation. With respect to the overall mutation spectrum, no mutations were identified in exon 11 (0/7) in this set of German families. These findings differed significantly from those in British (17/32)(P 5 0.012) and Southern Swedish (13/15) (P , 0.001) families. The lack of BRCA1 mutations in exon 11 which represents 61% of the entire coding sequence may provide additional insight into BRCA1 associated breast and ovarian tumor development.