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Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families
  1. D G R Evans1,
  2. S L Neuhausen2,
  3. M Bulman1,
  4. K Young1,
  5. D Gokhale1,
  6. F Lalloo1
  1. 1Academic Unit of Medical Genetics, Regional Genetics Service and National Genetics Reference Laboratory, St Mary’s Hospital, Manchester M13 0JH, UK
  2. 2Division of Epidemiology, Department of Medicine, University of California, IIrvine, CA, USA
  1. Correspondence to:
 Professor D G R Evans
 Consultant Clinical Geneticist, Academic Unit of Medical Genetics and Regional Genetic Service, St. Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK;

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The 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.1 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.2 Population studies have shown that the 185delAG mutation predates the separation of the Sephardi and Ashkenazi Jewish populations and is probably 2000 years old.3


Full gene screening for mutations in the northwest of England has identified two recurrent mutations.4BRCA1 4182delAATC (4184del TCAA or 4184del4) is a frameshift mutation that results in a stop at codon 1364, causing a truncated protein product. This mutation has been reported 75 times in the Breast Cancer Information Core (BIC) website ( In one study, it was identified in breast cancer cases in Britain, France, and the United States.6 The mutation was associated with three different haplotypes, indicating that it is a recurrent rather than a founder mutation. BRCA2 2157delG is also a frameshift mutation resulting in a stop at codon 659, causing a truncated protein product. …

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