ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.683G>T (p.Gly228Val)

dbSNP: rs1554302319
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540971 SCV000625675 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-04-28 criteria provided, single submitter clinical testing 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. 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 not expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 455734). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 228 of the PMS2 protein (p.Gly228Val).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589861 SCV000697357 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.683G>T (p.Gly228Val) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121412 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589861 SCV000889638 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001178551 SCV001343017 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing This missense variant replaces glycine with valine at codon 228 of the PMS2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics RCV001178551 SCV002665448 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-02 criteria provided, single submitter clinical testing The p.G228V variant (also known as c.683G>T), located in coding exon 6 of the PMS2 gene, results from a G to T substitution at nucleotide position 683. The glycine at codon 228 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is highly 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.

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