The need to answer the question “how much of the familial risk is currently explained by the known genes?” has increased ,and although BRCA1 and BRCA2 are considered the two major breast cancer (BC) susceptibility genes, they do not justify the entire percentage of all hereditary BC cases. The current consensus is that other BC predisposing genes could explain at least a portion of the remaining non-mutated familial cases, including not only other highpenetrance BC genes, but also moderate and low-penetrance genes. Considering these three different categories of genes, a gap of risk estimation in breast cancer can be observed. Moreover, different researchers tried to give significance to the mutations identified in terms of family management but the way in which these common variants contribute to cancer is still largely unknown.
It has been recently proposed that the ‘rare variant hypothesis’, a model in which the summation of the effects of a series of low frequency gene variants, could justify a great portion of the inherited susceptibility to relatively common human diseases, such as breast cancer, independently by their way of acting. However, this hypothesis is still debated due the fact that there is little or no evidence about the fitness effects of common, disease-associated variants.
Keywords: Breast cancer, high-penetrance genes, low-moderate penetrance genes, Cancer Risk, BRCA1, BRCA2, hereditary breast cancer, rare variant hypothesis, gene variants, disease-associated variants
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