Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Clendenning, M ; Senter, L ; Hampel, H ; Lagerstedt Robinson, K ; Sun, S ; Buchanan, D ; Walsh, M D ; Nilbert, Mef LU ; Green, J and Potter, J , et al. (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)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
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 (&lt;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 &lt;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 &gt;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}},
}