ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.641T>G (p.Val214Gly)

dbSNP: rs864622706
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206866 SCV000261967 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 214 of the PMS2 protein (p.Val214Gly). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 220964). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. 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.
GeneDx RCV000759926 SCV000565387 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.641T>G at the cDNA level, p.Val214Gly (V214G) at the protein level, and results in the change of a Valine to a Glycine (GTG>GGG). This variant has been reported in at least one individual with mismatch repair-deficient colorectal cancer (Le 2017). PMS2 Val214Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Val214Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000584176 SCV000691093 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces valine with glycine at codon 214 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/251484 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759926 SCV000889636 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000584176 SCV002658921 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-05 criteria provided, single submitter clinical testing The p.V214G variant (also known as c.641T>G), located in coding exon 6 of the PMS2 gene, results from a T to G substitution at nucleotide position 641. The valine at codon 214 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003462393 SCV004205492 uncertain significance Lynch syndrome 4 2023-08-04 criteria provided, single submitter clinical testing

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