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A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome
  1. Mark Clendenning (mark.clendenning{at}osumc.edu)
  1. The Ohio State University, United States
    1. Leigha Senter (leigha.senter{at}osumc.edu)
    1. The Ohio State University, United States
      1. Heather Hampel (heather.hampel{at}osumc.edu)
      1. The Ohio State University, United States
        1. Kristina Lagerstedt Robinson (kristina.lagerstedt{at}ki.se)
        1. Karolinska Institute, Sweden
          1. Shuying Sun (ssun{at}math.ohio-state.edu)
          1. The Ohio State University, United States
            1. Daniel Buchanan (daniel.buchanan{at}qimr.edu.au)
            1. Queensland Institute for Medical Research, Australia
              1. Michael D Walsh (michael.walsh{at}qimr.edu.au)
              1. Queensland Institute for Medical Research, Australia
                1. Mef Nilbert (mef.nilbert{at}med.lu.se)
                1. Lund University, Sweden
                  1. Jane S Green (janeg{at}mun.ca)
                  1. Memorial University of Newfoundland, Canada
                    1. John Potter (jpotter{at}fhcrc.org)
                    1. Fred Hutchinson Cancer Research Center, United States
                      1. Annika Lindblom (annika.lindblom{at}ki.se)
                      1. Karolinska Institute, Sweden
                        1. Albert de la Chapelle (albert.delachapelle{at}osumc.edu)
                        1. The Ohio State University, United States

                          Abstract

                          Background: 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.

                          Methods: 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.

                          Results: 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 < 0.05) at a SNP in exon 11, and have been shown to possess a short common haplotype; allowing us to calculate that the mutation arose around 1625 years ago (65 generations; 95% CI: [22, 120]).

                          Discussion: Ancestral analysis indicates that this mutation is enriched in individuals with British and Swedish ancestry. We estimate that there are >10,000 carriers of this mutation in the United States 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.

                          • Age calculation
                          • Founder effect
                          • Lynch syndrome
                          • PMS2

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