ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.614A>C (p.Gln205Pro) (rs587779342)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164809 SCV000215490 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-29 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Structural Evidence
Invitae RCV000524477 SCV000285143 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 205 of the PMS2 protein (p.Gln205Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant was reported in one individual with a personal history consistent with constitutional mismatch repair deficiency syndrome (PMID: 18602922), In addition to the c.614A>C variant, this individual carried a second PMS2 pathogenic variant. Immunohistochemistry results from the tumors of this patient showed absence of PMS2 expression. This variant has also been reported in a patient with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 91361). Experimental studies have shown that this missense change results in reduced mismatch repair activity (PMID: 24027009). 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.
Counsyl RCV000409570 SCV000489243 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000485945 SCV000567507 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.614A>C at the cDNA level, p.Gln205Pro (Q205P) at the protein level, and results in the change of a Glutamine to a Proline (CAG>CCG). PMS2 Gln205Pro was observed in at least two individuals with a personal or family history of Lynch syndrome-associated tumors (Yurgelun 2015, van der Klift 2016). Senter et al. (2008) reported this variant to co-occur with a PMS2 pathogenic variant in an individual with lymphoma, early-onset colon, and duodenal cancer for whom at least one tumor demonstrated loss of PMS2 expression on immunohistochemistry. While two siblings of this individual had brain tumors, no other Lynch-related tumors were reported in this kindred. An in vitro mismatch repair functional assay demonstrated that the repair efficiency of PMS2 Gln205Pro is significantly higher than that of a pathogenic control but compromised when compared to wild-type (Drost 2013). PMS2 Gln205Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as uncertain due to insufficient evidence (Thompson 2014). Despite some evidence suggesting pathogenicity, based on currently available evidence, it is unclear whether PMS2 Gln205Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000164809 SCV000691091 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-09 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000409570 SCV000840046 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-11-03 criteria provided, single submitter clinical testing A heterozygous c.614A>C (p.Q205P) likely pathogenic variant in the PMS2 gene was detected in this individual. This variant has been previously described as disease-causing in mismatch repair cancer syndrome (PMID: 18602922, 25980754), an autosomal recessive cancer predisposition syndrome. In addition, functional studies have indicated that the p.Q205P change alters PMS2 enzymatic function (PMID: 24027009). Therefore, we consider this variant to be likely pathogenic.

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