PMS2 – Lynch syndrome

Postmeiotic segregation increased 2 (PMS2) Gene Symbol encodes a MutLα subunit essential for DNA mismatch repair. Monoallelic germline variants in PMS2 cause Lynch syndrome, an autosomal dominant cancer predisposition marked by microsatellite instability (MSI) and elevated risks for colorectal, endometrial, and other tumors (PMID:21204794).

Extensive genetic screening of 396 LS-suspected probands identified 52 distinct pathogenic PMS2 variants in 121 probands (PMID:27435373), including frameshift, nonsense, splice-site, and deleterious missense changes. Segregation of heterozygous PMS2 alleles with disease in multiple families supports an autosomal dominant inheritance pattern with variable penetrance.

The variant spectrum comprises at least 24 frameshift, 18 nonsense, 8 splice-site, and numerous missense mutations with demonstrated functional impact. A recurrent founder allele c.736_741del (p.Pro246_Pro247del) was observed in 12 ostensibly unrelated LS families of Northern European ancestry, suggesting a 1,625-year-old origin (PMID:18178629).

Functional assays reveal that loss of PMS2 expression on immunohistochemistry correlates with MSI phenotypes. Pms2-deficient murine and human cells exhibit elevated somatic hypermutation and tandem base substitutions, implicating PMS2 in repair of adjacent mispairs (PMID:9618520). In vitro studies of the PMS2-E705K endonuclease motif mutation show defective mismatch repair, recombination suppression, and apoptotic response to DNA damage (PMID:20864418).

Technical challenges arise from PMS2 pseudogenes that confound genomic analyses. RNA-based cDNA sequencing effectively circumvents pseudogene interference, enabling accurate detection of splice defects and truncating mutations (e.g., c.182del (p.Tyr61LeufsTer15)) in constitutional mismatch repair deficiency (PMID:15077197; PMID:18030674).

In summary, heterozygous PMS2 variants are definitively implicated in Lynch syndrome. Clinical diagnosis should integrate tumor MSI/IHC prescreening with comprehensive germline testing—including pseudogene-aware methods—to guide surveillance and prophylactic interventions. Key take-home: PMS2 analysis is critical for precise Lynch syndrome diagnosis and management.

References

• Clinical genetics • 2011 • Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations. PMID:21204794
• Human mutation • 2016 • Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. PMID:27435373
• Journal of medical genetics • 2008 • A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. PMID:18178629
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. PMID:9618520
• DNA repair • 2010 • Conservation of functional asymmetry in the mammalian MutLα ATPase PMID:20864418
• American journal of human genetics • 2004 • Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. PMID:15077197
• Human mutation • 2007 • RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. PMID:18030674

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