ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.466A>G (p.Thr156Ala) (rs786204206)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168296 SCV000218975 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 156 of the PMS2 protein (p.Thr156Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colon and breast cancer (PMID: 26320870). ClinVar contains an entry for this variant (Variation ID: 188304). 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, 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.
GeneDx RCV000485878 SCV000565383 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.466A>G at the cDNA level, p.Thr156Ala (T156A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has been identified in an individual with colon and breast cancer (Li 2015). Functional studies have shown that this residue is phosphorylated and that this variant results in the loss of phosphorylation and increased stability of the PMS2 protein (Jia 2013). PMS2 Thr156Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Thr156Ala is located in motif IV of the ATPase domain (Guarne 2001). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether PMS2 Thr156Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000662566 SCV000785168 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-05-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV001022873 SCV001184658 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-20 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001022873 SCV001360036 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-26 criteria provided, single submitter clinical testing

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