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A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

2008; BMJ; Volume: 45; Issue: 6 Linguagem: Inglês

10.1136/jmg.2007.056150

1468-6244

Mark Clendenning, Leigha Senter, Heather Hampel, Kristina Lagerstedt‐Robinson, Shuxin Sun, Daniel D. Buchanan, Michael D. Walsh, Mef Nilbert, J. Green, John D. Potter, Annika Lindblom, Albert de la Chapelle,

DNA Repair Mechanisms

When compared to the other mismatch repair genes involved in Lynch syndrome, the identification of mutations within PMS2 has been limited (<2% of all identified mutations), yet the immunohistochemical analysis of tumour samples indicates that approximately 5% of Lynch syndrome cases are caused by PMS2. This disparity is primarily due to complications in the study of this gene caused by interference from pseudogene sequences.Using a recently developed method for detecting PMS2 specific mutations, we have screened 99 patients who are likely candidates for PMS2 mutations based on immunohistochemical analysis.We have identified a frequently occurring frame-shift mutation (c.736_741del6ins11) in 12 ostensibly unrelated Lynch syndrome patients (20% of patients we have identified with a deleterious mutation in PMS2, n = 61). These individuals all display the rare allele (population frequency 10 000 carriers of this mutation in the USA alone. The identification of both the mutation and the common haplotype in one Swedish control sample (n = 225), along with evidence that Lynch syndrome associated cancers are rarer than expected in the probands' families, would suggest that this is a prevalent mutation with reduced penetrance.