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 single nucleotide polymorphism (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% confidence interval 22 to 120). CONCLUSION: 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 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.
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 syndromepatients (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 single nucleotide polymorphism (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% confidence interval 22 to 120). CONCLUSION: 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 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.
Authors: Michel De Vos; Bruce E Hayward; Ruth Charlton; Graham R Taylor; Adam W Glaser; Susan Picton; Trevor R Cole; Eamonn R Maher; Carole M E McKeown; Jill R Mann; John R Yates; Diana Baralle; Julia Rankin; David T Bonthron; Eamonn Sheridan Journal: J Natl Cancer Inst Date: 2006-03-01 Impact factor: 13.506
Authors: Daniel L Worthley; Michael D Walsh; Melissa Barker; Andrew Ruszkiewicz; Graeme Bennett; Kerry Phillips; Graeme Suthers Journal: Gastroenterology Date: 2005-05 Impact factor: 22.682
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Authors: A Hemminki; P Peltomäki; J P Mecklin; H Järvinen; R Salovaara; M Nyström-Lahti; A de la Chapelle; L A Aaltonen Journal: Nat Genet Date: 1994-12 Impact factor: 38.330
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Authors: Paul J Limburg; William S Harmsen; Helen H Chen; Steven Gallinger; Robert W Haile; John A Baron; Graham Casey; Michael O Woods; Stephen N Thibodeau; Noralane M Lindor Journal: Clin Gastroenterol Hepatol Date: 2010-11-05 Impact factor: 11.382
Authors: M O Woods; H B Younghusband; P S Parfrey; S Gallinger; J McLaughlin; E Dicks; S Stuckless; A Pollett; B Bapat; M Mrkonjic; A de la Chapelle; M Clendenning; S N Thibodeau; M Simms; A Dohey; P Williams; D Robb; C Searle; J S Green; R C Green Journal: Gut Date: 2010-08-03 Impact factor: 23.059
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Authors: J Tomsic; L Senter; S Liyanarachchi; M Clendenning; C P Vaughn; M A Jenkins; J L Hopper; J Young; W Samowitz; A de la Chapelle Journal: Clin Genet Date: 2012-06-04 Impact factor: 4.438
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