ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1454C>T (p.Thr485Met) (rs1805323)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570329 SCV000664907 likely benign Hereditary cancer-predisposing syndrome 2016-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
GeneDx RCV000479471 SCV000565407 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1454C>T at the cDNA level, p.Thr485Met (T485M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). 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 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 Thr485Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227437 SCV000285070 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 485 of the PMS2 protein (p.Thr485Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs1805323, ExAC 0.001%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 237886). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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