Advanced

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
, et al. (More)
(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
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
2008-09-12 15:35:14
date last changed
2017-01-01 06:16:07
@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},
  volume       = {45},
  year         = {2008},
}