PMS1

Inheritance Pattern: AD

Disease ID:MONDO:0005835

Submitter: ClinGen

*PMS1* (formerly known as PMSL1) encodes a protein belonging to the DNA mismatch repair mutL/hexB family, suggesting its involvement in DNA mismatch repair. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is no disease associated with *PMS1* in OMIM, although there was an early assertion of association with Lynch syndrome. Thus, it was curated for that disorder. **Summary of Genetic Evidence (Case Level):** 0 point Nicolaides et al., 1994, first reported a frameshift germline variant in *PMS1* associated with autosomal dominant hereditary non-polyposis colorectal cancer/Lynch syndrome (PMID: 8072530). However, conflicting findings were subsequently noted in another study (Liu et al., 2001, PMID:11691795), where the proband and her nephew with Lynch syndrome reported in PMID: 8072530, in fact, had a large deletion in *MSH2* but not *PMS1*. Liu et al. also failed to detect pathogenic germline mutations in *PMS1* from 84 families with Lynch syndrome. Another study also found no germline variants in PMS1 within 34 Lynch syndrome families (PMID: 8574961). **Summary of Experimental Evidence:** 0.5 point While a study highlighted the association of PMS1 with hMLH1 as a heterodimer (PMID: 10748105), Prolla et al. (PMID:9500552) generated mice deficient for the murine homologues of the human gene *PMS1* and showed that the mice did not develop tumors, and mouse embryonic fibroblast cells deficient for PMS1 showed no defeat in dinucleotide repeats and there was no significant difference of microsatellite instability in the mucosa of PMS-deficient mice compared to wildtypes. **Overall Summary:** Considering the lack of substantial association in both genetic and experimental studies, there is convincing evidence refuting the gene-disease relationship between *PMS1* and autosomal dominant Lynch syndrome. This gene-disease pair was originally evaluated as disputed on 5/22/2017 by Colon Cancer GCEP. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 8/25/2023 (SOP Version 9).