ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.346G>A (p.Ala116Thr)

gnomAD frequency: 0.00001  dbSNP: rs751799116
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479343 SCV000570279 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.346G>A at the cDNA level, p.Ala116Thr (A116T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Ala116Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Ala116Thr occurs at a position that is conserved across species and is located within the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PMS2 Ala116Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000550215 SCV000625639 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 116 of the PMS2 protein (p.Ala116Thr). This variant is present in population databases (rs751799116, 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: 421163). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. 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.
Ambry Genetics RCV001020378 SCV001181851 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-11 criteria provided, single submitter clinical testing The p.A116T variant (also known as c.346G>A), located in coding exon 4 of the PMS2 gene, results from a G to A substitution at nucleotide position 346. The alanine at codon 116 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001020378 SCV001341284 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 116 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 hereditary cancer in the literature. This variant has been identified in 2/266610 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.
Baylor Genetics RCV003470566 SCV004205470 uncertain significance Lynch syndrome 4 2023-08-27 criteria provided, single submitter clinical testing

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