The APC gene is mutated in the germline of people from families where there is a predisposition to develop polyposis coli.

The APC gene was investigated in 31 unrelated polyposis coli families by SSCP analysis and the protein truncation test. Twenty-three germline mutations were identified which gave rise to a variety of different phenotypes. Some of these mutations have already been described; however we report six previously unpublished mutations. Typical disease symptoms were observed in families who harboured mutations between exon 4 (codon 169) and codon 1393 of exon 15. Mutations beyond codon 1403 were associated with more varied phenotype with respect to the development of extracolonic symptoms. In this report we provide support for the notion that there appears to be a correlation between the location of an APC mutation (beyond codon 1403) and extracolonic manifestations of familial adenomatous polyposis. (J Med Genet 1996;33:274-280)

In this study we investigated 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. We identified four germline mutations in three breast cancer families and in one breast-ovarian cancer family. Among these were one frameshift mutation, one nonsense mutation, one novel splice site mutation, and one missense mutation. The missense mutation was also found in 2.8% of the general population, suggesting that it is not disease associated. The average age of disease onset in those families harbouring causative mutations was between 32.3 and 37.4 years, whereas the family harbouring the missense mutation had an average age of onset of 51.2 years. In this study, 45 German breast/ovarian cancer families have been systematically studied for germline mutations in the BRCA1 gene.The entire coding sequence of the BRCA1 gene was screened using single strand conformational polymorphism (SSCP) analysis, the protein truncation test (PTT), followed by sequencing analysis. The results confirm previous findings with respect to the paucity of mutations in exon 1 1 in the German population and that only a small proportion of families exhibiting an aggregation of early onset breast cancer appears to be the result of mutations in the BRCA1 gene. Material and methods FAMILIESForty-five families, 37 breast cancer families and eight breast-ovarian cancer families of German origin, were analysed in this study. All families contained three or more affected members with at least two diagnosed under the age of 60 years. Thirty-two of these families were previously included in a linkage study.

Germline mutations in the BRCA1 gene have been associated with familial breast/ ovarian cancer in large families showing high penetrance of the disease. Little is known, however, about the contribution of BRCA1 mutations to breast/ovarian cancer in small families with few affected members or in isolated early onset cases. Therefore we examined the BRCA1 gene in 63 breast/ovarian cancer patients who either came from small families with as few as one affected first degree relative, or in patients who had no family history but had developed breast cancer under 40 years of age. Using the protein truncation test, we were able to identify three unique BRCA1 germline mutations (4.8%). Two of the probands had only one affected first degree and several second degree relatives and the third had three affected first degree relatives including two sisters who, when tested, were also found to carry the mutation. There was no family history of ovarian cancer in any of the three families. (T Med Genet 1996;33:721-725) Key words: breast cancer; BRCA1; mutations.There are many factors associated with a woman's risk of developing breast cancer but by far the most consistent is a positive family history of the disease.' Hereditary breast cancer is characterised by a relatively early onset, an excess of bilateral disease, and in some families an over-representation of ovarian cancer and to a lesser extent other malignancies, such as colorectal and prostate cancer.2 Segregation analysis provided evidence that familial breast cancer could be attributed to one or more highly penetrant autosomal dominant susceptibility genes.3In 1990, a breast cancer susceptibility locus (BRCA1) was mapped to chromosome 17q21.4 The Breast Cancer Linkage Consortium confirmed these findings using 214 families having high numbers of breast and ovarian cancer patients,5 and further refined the locus.