ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1268C>G (p.Ala423Gly) (rs756883400)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164345 SCV000214978 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524430 SCV000285058 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 423 of the PMS2 protein (p.Ala423Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs756883400, ExAC 0.009%). This variant was reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 184994). 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.
Illumina Clinical Services Laboratory,Illumina RCV000234512 SCV000469735 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000657013 SCV000566388 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1268C>G at the cDNA level, p.Ala423Gly (A423G) at the protein level, and results in the change of an Alanine to a Glycine (GCC>GGC). This variant was identified in 1/1260 individuals undergoing testing for Lynch syndrome due to a personal history of a Lynch-associated cancer and/or polyps; of note, this individual also harbored a pathogenic MLH1 variant (Yurgelun 2015). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology. This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Ala423Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486789 SCV000601812 uncertain significance not specified 2017-05-28 criteria provided, single submitter clinical testing
Color RCV000164345 SCV000686116 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing

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