ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.137G>A (p.Ser46Asn) (rs121434629)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076806 SCV000592922 likely pathogenic Lynch syndrome 2014-12-11 criteria provided, single submitter clinical testing
Invitae RCV000524431 SCV000552059 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 46 of the PMS2 protein (p.Ser46Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs121434629, ExAC 0.003%). This variant has been reported in individuals with a personal or family history of colorectal cancer and sebaceous adenoma (PMID: 26866578, 25006859). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 18273873). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 91301). Experimental studies have shown that this missense change disrupts PMS2 mismatch repair activity (PMID: 24027009). A different missense substitution at this codon (p.Ser46Ile) has been determined to be pathogenic (PMID: 22577899, 23709753). This suggests that the serine residue is critical for PMS2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000584471 SCV000691980 pathogenic not provided no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000584471 SCV000888391 likely pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.