A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome
(2008) In Journal of Medical Genetics 45(6). p.340-345- 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_741del 6ins11) in 12 ostensibly... (More)
- 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_741del 6ins11) 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. (Less)
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- author
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Medical Genetics
- volume
- 45
- issue
- 6
- pages
- 340 - 345
- publisher
- BMJ Publishing Group
- external identifiers
-
- wos:000256369500003
- scopus:45249083654
- pmid:18178629
- ISSN
- 0022-2593
- DOI
- 10.1136/jmg.2007.056150
- language
- English
- LU publication?
- yes
- id
- 1e2b624c-2ee1-43ff-a0b6-dea2e4a8a974 (old id 1201190)
- date added to LUP
- 2016-04-01 14:29:01
- date last changed
- 2022-01-28 00:51:51
@article{1e2b624c-2ee1-43ff-a0b6-dea2e4a8a974, 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_741del 6ins11) 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.}}, author = {{Clendenning, M and Senter, L and Hampel, H and Lagerstedt Robinson, K and Sun, S and Buchanan, D and Walsh, M D and Nilbert, Mef and Green, J and Potter, J and Lindblom, A and de la Chapelle, A}}, issn = {{0022-2593}}, language = {{eng}}, number = {{6}}, pages = {{340--345}}, publisher = {{BMJ Publishing Group}}, series = {{Journal of Medical Genetics}}, title = {{A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome}}, url = {{http://dx.doi.org/10.1136/jmg.2007.056150}}, doi = {{10.1136/jmg.2007.056150}}, volume = {{45}}, year = {{2008}}, }