ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1499C>G (p.Ser500Cys) (rs375905814)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478044 SCV000567104 uncertain significance not provided 2015-06-30 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1499C>G at the cDNA level, p.Ser500Cys (S500C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ser500Cys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ser500Cys occurs at a position that is not conserved and is not located in a known functional domain (Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PMS2 Ser500Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000525015 SCV000625529 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 500 of the PMS2 protein (p.Ser500Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs375905814, ExAC 0.01%). This variant has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 419358). 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, this variant has uncertain impact on PMS2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563556 SCV000663529 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-31 criteria provided, single submitter clinical testing Insufficient evidence

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