TY - JOUR

T1 - A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome

AU - Clendenning, Mark

AU - Senter, Leigha

AU - Hampel, Heather

AU - Robinson, Kristina Lagerstedt

AU - Sun, Shuying

AU - Buchanan, Daniel

AU - Walsh, Michael D

AU - Nilbert, Mef

AU - Green, Jane S

AU - Potter, John

AU - Lindblom, Annika

AU - de la Chapelle, Albert

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - http://dx.doi.org/10.1136/jmg.2007.056150

DO - http://dx.doi.org/10.1136/jmg.2007.056150

M3 - Journal article

VL - 45

SP - 340

EP - 345

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

ER -