ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.880C>T (p.Arg294Trp) (rs563433235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212854 SCV000149617 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.880C>T at the cDNA level, p.Arg294Trp (R294W) 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 pathogenic or benign. Arg294Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Arg294Trp is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether PMS2 Arg294Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115708 SCV000187600 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168085 SCV000218739 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 294 of the PMS2 protein (p.Arg294Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs563433235, ExAC 0.03%). This variant has been observed in an individual affected with breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 127799). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The tryptophan 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.
Color RCV000115708 SCV000686250 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing

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