Identification of personal risk of breast cancer: genetics

A second major breast cancer susceptibility gene, BRCA2, was mapped to chromosome 13q in 1994 shortly before the sequence of the BRCA1 gene was clarified and family-specific disease-causing mutations started to be reported [5,6]. The full BRCA2 gene sequence was reported in 1995 [7]. Families with mutations in the BRCA2 gene were noted to be more likely to contain a male breast cancer case than might be expected by chance (and more than had been seen in families due to BRCA1 mutations); ovarian and fallopian tube cancers still occurred with increased frequency but overall not as frequently as in BRCA1-associated families. With the discovery of the correct gene sequences for BRCA1 and BRCA2 it became possible to offer predictive genetic testing to members of families in which the causative gene mutation had been identified. Predictive testing for breast cancer susceptibility was introduced as a clinical service from the mid-1990s in some centres in the UK [8]. Families in which mutations were identified through research studies were the first to be informed [9]. Many of these families had been identified because of their high incidence of cancer, and so inevitably the estimated lifetime chance that a carrier of one of these genes would develop cancer was high [10,11].The BRCA1 and BRCA2 genes are very large, and mutation testing was either very expensive (in the USA) or very slow (in European countries) when it first became available. It soon became clear that mutations in these genes accounted for a relatively small proportion of all families with breast cancer clusters. Families with four or more cancer cases developing at young age, particularly those families in which ovarian cancers occurred, were more likely to yield pathogenic mutations when DNA from a cancer-affected family member was screened for mutations. Smaller clusters of later onset cancers, although clearly familial, were noted to have a much lower probability of harbouring a BRCA1 or BRCA2 mutation [