PMS1 – Lynch syndrome

PMS1 has been investigated as a minor DNA mismatch repair (MMR) gene in hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome. Early genetic screening of familial colorectal cancer patients identified MMR gene mutations in approximately 3% of cases, with PMS1 among the genes analyzed (PMID:10544223). However, subsequent large‐scale analyses in Brazilian cohorts found no pathogenic PMS1 variants among 82 patients negative for MLH1 and MSH2 mutations (PMID:26437257). A rare PMS1 c.605G>A (p.Arg202Lys) variant studied in discordant sisters from hereditary breast cancer families did not segregate with disease nor affect exon 6 splicing, supporting its likely benign status (PMID:34852986).

Functional assays in Saccharomyces cerevisiae demonstrate that complete loss of PMS1 results in a 390-fold increase in GT tract instability, underscoring its role in MMR and microsatellite maintenance (PMID:9630599). Despite this, the absence of confirmed pathogenic PMS1 variants co-segregating with Lynch syndrome and the lack of recurrent or founder mutations in human studies argue against a major clinical role. PMS1 remains a gene of uncertain clinical utility in Lynch syndrome testing.

Key take-home: Current human genetic evidence does not support PMS1 as a standalone susceptibility gene for Lynch syndrome; its testing should be interpreted cautiously and within multi‐gene panel contexts.

References

• Journal of medical genetics • 1999 • Genetic susceptibility to non-polyposis colorectal cancer. PMID:10544223
• PloS one • 2015 • Clinical and Molecular Characterization of Brazilian Patients Suspected to Have Lynch Syndrome. PMID:26437257
• Cancer genetics • 2022 • Investigation of discordant sibling pairs from hereditary breast cancer families and analysis of a rare PMS1 variant. PMID:34852986
• Gene • 1998 • Functional genetic tests of DNA mismatch repair protein activity in Saccharomyces cerevisiae. PMID:9630599

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