ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.608C>G (p.Thr203Ser) (rs779946576)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166541 SCV000217342 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000166541 SCV000911786 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000509403 SCV000279133 uncertain significance not provided 2018-05-20 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.608C>G at the cDNA level, p.Thr203Ser (T203S) at the protein level, and results in the change of a Threonine to a Serine (ACC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr203Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Thr203Ser is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether PMS2 Thr203Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000509403 SCV000607361 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000463624 SCV000552053 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 203 of the PMS2 protein (p.Thr203Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs779946576, ExAC 0.003%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186883). 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 serine 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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