ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1279C>T (p.Arg427Cys) (rs376042544)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115655 SCV000149564 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1279C>T at the cDNA level, p.Arg427Cys (R427C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population 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 a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Arg427Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228417 SCV000285059 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 427 of the PMS2 protein (p.Arg427Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs376042544, ExAC 0.05%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127758). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000565134 SCV000663455 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000565134 SCV000686118 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115655 SCV001134577 uncertain significance not provided 2019-08-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000115655 SCV001371515 uncertain significance not provided 2020-05-01 criteria provided, single submitter clinical testing

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