Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families.

T he prevalence of BRCA1 and BRCA2 mutations in families with breast and ovarian cancers depends on the type of cancer found, the number of cases, and the ethnic background of the family. The proportion of breast cancers attributable to BRCA1 or BRCA2 may also depend on the ethnic origin of families. Several mutations have been identified that are found only in specific countries or ethnic groups, suggesting that they are founder mutations. Individuals with the same founder mutation will also share the same alleles at polymorphic markers within the gene or adjacent to the gene. Some common mutations do not segregate with the same alleles and are therefore recurrent mutations. They occur at ‘hot spots’ for mutation; unstable parts of the gene. In countries with a small founder population, very few mutations may account for the vast majority of breast cancer families. The Ashkenazi Jewish population have three founder mutations, which are found in 2% of the Ashkenazi Jewish population. Population studies have shown that the 185delAG mutation predates the separation of the Sephardi and Ashkenazi Jewish populations and is probably 2000 years old.