ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1438G>A (p.Gly480Arg) (rs146848345)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205844 SCV000260965 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 480 of the PMS2 protein (p.Gly480Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs146848345, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 220433). 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 tolerated, 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.
Ambry Genetics RCV000219384 SCV000273837 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000215100 SCV000279139 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1438G>A at the cDNA level, p.Gly480Arg (G480R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has been observed in at least one individual with advanced cancer undergoing multi-gene panel testing (Mandelker 2017). 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). PMS2 Gly480Arg is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Gly480Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000215100 SCV000885993 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Color RCV000219384 SCV000911029 likely benign Hereditary cancer-predisposing syndrome 2016-08-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780614 SCV000918032 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1438G>A (p.Gly480Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246264 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1438G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000215100 SCV001134580 uncertain significance not provided 2019-04-21 criteria provided, single submitter clinical testing

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