Breast cancer is the most common form of cancer found in women and a number of risk factors for developing the disease are known. Among these factors a family history of the disease remains the single most important risk factor. Between 5-10% of all breast cancer cases have a familial component and knowledge of the genetic basis of disease in these families enables cancer prevention strategies. Linkage analysis of breast cancer families with specific phenotypes in the early nineties lead to identification of the two major breast cancer predisposing genes, BRCA1 and BRCA2. Although mutations in BRCA1 and BRCA2 account for the majority of early-onset breast and breast-ovarian cancer families, there remains a significant proportion of families where disease is not linked to either of these genes. Since the discovery of BRCA1 and BRCA2 the search has continued for BRCA3 and this difficult task has been hampered by genetic heterogeneity and the lack of distinct phenotypes to classify non-BRCA1/BRCA2 families. The combination of different techniques could facilitate the identification of more genetically homogenous sub-groups which may allow progress in the identification of BRCA3. The remainder of non-BRCA1/BRCA2 breast cancer families may not segregate high- or moderate- penetrance genes and instead disease may be due to a number of low-penetrance alleles. Identification, characterisation and validation of these numerous low-penetrance alleles remains a formidable task in the search for novel breast cancer genes.
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