ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.346G>A (p.Ala116Thr) (rs751799116)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479343 SCV000570279 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.346G>A at the cDNA level, p.Ala116Thr (A116T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala116Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala116Thr occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). 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 Ala116Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000550215 SCV000625639 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 116 of the PMS2 protein (p.Ala116Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs751799116, ExAC 0.002%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 421163). 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: "Deleterious"; PolyPhen-2: "Probably 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 RCV001020378 SCV001181851 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001020378 SCV001341284 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing

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