ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2249G>A (p.Gly750Asp) (rs587779337)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212868 SCV000149588 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2249G>A at the cDNA level, p.Gly750Asp (G750D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGC>GAC). This variant has been reported to co-occur with a PMS2 frameshift or deletion variant in three adult individuals with multiple primary cancers suggestive of later onset congenital mismatch repair deficiency (CMMR-D) and loss of PMS2 via mismatch repair (MMR) immunohistochemistry in both tumor and adjacent unaffected tissue/lymphocytes (Senter 2008, van Galen 2010, Bodo 2015). Of note, in one case the variants were in trans (Senter 2008), but phase was not confirmed in the other two individuals (van Galen 2010, Bodo 2015). PMS2 Gly750Asp has also been reported to co-occur with a pathogenic PMS2 variant in an individual with colorectal cancer whose tumor displayed isolated loss of PMS2, but normal tissue was not tested (Goodenberger 2016). An immortalized lymphoblastoid cell line from the individual reported in Bodo et al. (2015) was shown to have an MMR phenotype displaying microsatellite instability and tolerance to methylating agents. Additionally, an in vitro functional assay demonstrated that this variant had reduced, though not deficient, MMR activity, suggesting that it may be pathogenic but with reduced penetrance (Drost 2013). PMS2 Gly750Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Gly750Asp is located in the endonuclease domain (Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. As PMS2 Gly750Asp has only been reported in individuals also carrying PMS2 pathogenic variants with cancers diagnosed at older than expected ages for typical CMMR-D and MMR activity has been observed to be reduced but not abolished, there is reason to believe that this variant may be hypomorphic. While there is evidence supporting that PMS2 Gly750Asp predisposes to CMMR-D when in trans with a pathogenic PMS2 variant, there is no evidence to support an increased cancer risk in the heterozygous state. Therefore, we are unable to determine if PMS2 Gly750Asp would cause Lynch syndrome, and consider it to be a variant of uncertain significance in this respect. Regarding CMMR-D, if this individual's partner carries a PMS2 pathogenic variant, there would be a 25% chance for each of their children to have both variants and possibly develop features consistent with CMMR-D.
Ambry Genetics RCV000115679 SCV000172925 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence
Invitae RCV000524463 SCV000551998 likely pathogenic Hereditary nonpolyposis colon cancer 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 750 of the PMS2 protein (p.Gly750Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in individuals with constitutional mismatch repair deficiency syndrome (PMID: 18602922, 26318770, https://hccpjournal.biomedcentral.com/articles/10.1186/1897-4287-9-S1-P38). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been observed to co-occur with a pathogenic variant in PMS2 in an individual with colorectal cancer (PMID: 25856668). This variant has been reported to affect PMS2 protein function (PMID: 24027009, 26116798). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076849 SCV000592948 uncertain significance Lynch syndrome 2014-12-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212868 SCV001155025 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing

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