ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2437C>T (p.Arg813Trp) (rs375968016)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656952 SCV000149596 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2437C>T at the cDNA level, p.Arg813Trp (R813W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in a zinc binding motif in the endonuclease domain (Kosinski 2008, Fukui 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg813Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115687 SCV000215363 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000196074 SCV000255293 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 813 of the PMS2 protein (p.Arg813Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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 not been reported in the literature in individuals with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127783). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago RCV000212874 SCV000596464 uncertain significance not specified 2016-10-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656952 SCV000888409 uncertain significance not provided 2019-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212874 SCV000918043 uncertain significance not specified 2017-10-26 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2437C>T (p.Arg813Trp) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 19/201724 control chromosomes at a frequency of 0.0000942, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136), and must be taken with caution due to multiple highly homologous pseudogenes. The variant was reported in one colorectal cancer case, but was not specified whether the mutation was germline or somatic in origin (Chang_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.

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