ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.11C>G (p.Ala4Gly) (rs745361721)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214339 SCV000276758 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;RNA Studies
GeneDx RCV000657052 SCV000279428 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.11C>G at the cDNA level, p.Ala4Gly (A4G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has been identified at similar frequencies between Icelandic colorectal cancer patients and controls (p=0.19) (Haraldsdottir 2017). PMS2 Ala4Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). PMS2 Ala4Gly is located in the ATPase domain (Guarne 2001). While protein-based in-silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether PMS2 Ala4Gly is pathogenic or benign. We consider PMS2 Ala4Gly to be a variant of uncertain significance.
Invitae RCV000230374 SCV000285051 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 4 of the PMS2 protein (p.Ala4Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs745361721, ExAC 0.009%). This variant has been observed in individuals affected with colorectal cancer and pancreatic cancer (PMID: 28466842, 25479140). ClinVar contains an entry for this variant (Variation ID: 232589). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000214339 SCV000686105 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000222258 SCV000731352 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Ala4Gly variant in PMS2 has not been previously reported in individuals wi th colorectal cancer, but has been identified in 1/11544 Latino chromosomes by t he Exome Aggregation Consortium (ExAC,; dbSNP rs7 45361721). While computational pathogenicity prediction tools and conservation a nalysis suggest that the p.Ala4Gly variant may not impact the protein, this vari ant is predicted to create a novel splice site. However, the accuracy of these tools is unknown and therefore this information is not predictive enough to dete rmine or rule out pathogenicity. In summary, the clinical significance of the p. Ala4Gly variant is uncertain.
Counsyl RCV000662535 SCV000785108 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-04-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000662535 SCV001322572 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2018-01-13 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.

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