ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1673_1674inv (p.Thr558Arg)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199238 SCV000255286 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-05-12 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 216869). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 558 of the PMS2 protein (p.Thr558Arg).
Ambry Genetics RCV000217307 SCV000276742 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-12 criteria provided, single submitter clinical testing The c.1673_1674delCCinsGG variant (also known as p.T558R), located in coding exon 11 of the PMS2 gene, results from the deletion of CC and insertion of GG at nucleotide positions 1673 and 1674 and causes the substitution of the threonine at codon 558 for arginine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000217307 SCV001345569 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces threonine with arginine at codon 558 of the PMS2 protein. 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 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.
GeneDx RCV002273984 SCV002559390 uncertain significance not provided 2022-08-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing but the protein effect of this missense change is unknown; Has not been previously published as pathogenic or benign to our knowledge

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