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Updated: Jul 8, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome
M Clendenning1, L Senter, H Hampel
1Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
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.
Insights
A common PMS2 mutation, c.736_741del6ins11, identified in Lynch syndrome patients, likely originated 1625 years ago. This prevalent mutation, with British and Swedish ancestry links, may have reduced penetrance.
Area of Science:
- Genetics
- Cancer Genomics
- Human Evolution
Background:
- Lynch syndrome is linked to mismatch repair gene mutations.
- PMS2 mutations are underrepresented in genetic screenings due to pseudogene interference.
- Immunohistochemistry suggests PMS2 accounts for ~5% of Lynch syndrome cases.
Purpose of the Study:
- To identify specific PMS2 mutations using a novel detection method.
- To investigate the prevalence and origin of a common PMS2 mutation.
- To assess the penetrance of a specific PMS2 mutation in Lynch syndrome.
Main Methods:
- Screening of 99 patients with suspected PMS2 mutations using a new detection method.
- Identification and characterization of a recurrent frame-shift mutation (c.736_741del6ins11).
- Haplotype analysis and SNP frequency assessment to determine mutation origin and population frequency.
Main Results:
- A recurrent PMS2 mutation (c.736_741del6ins11) was found in 12 Lynch syndrome patients.
- The mutation is associated with a rare allele at an exon 11 SNP and a common haplotype.
- Phylogenetic analysis estimates the mutation arose approximately 1625 years ago.
Conclusions:
- The c.736_741del6ins11 mutation is prevalent, particularly in individuals of British and Swedish ancestry.
- Over 10,000 carriers are estimated in the USA alone.
- Reduced cancer incidence in affected families suggests this PMS2 mutation may have reduced penetrance.
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