ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.40G>T (p.Ala14Ser) (rs876661039)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218140 SCV000279315 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.40G>T at the cDNA level, p.Ala14Ser (A14S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala14Ser was not observed in large population cohorts (Lek 2016). Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala14Ser occurs at a position that is not conserved and is located in the ATPase domain (Guarne 2001). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ala14Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000536772 SCV000625653 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 14 of the PMS2 protein (p.Ala14Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). 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: 234477). 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, 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 RCV000562665 SCV000670762 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000562665 SCV000906971 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218140 SCV001134602 uncertain significance not provided 2019-03-25 criteria provided, single submitter clinical testing

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