ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.607A>G (p.Thr203Ala)

dbSNP: rs730881907
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160881 SCV000211569 uncertain significance not provided 2014-05-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.607A>G at the cDNA level, p.Thr203Ala (T203A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Thr203Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Thr203Ala occurs at a position that is well conserved among mammals and is located in the ATPase domain (Fukui 2011). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Thr203Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001318819 SCV001509534 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-02-24 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: 182797). 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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 203 of the PMS2 protein (p.Thr203Ala).
Ambry Genetics RCV002354405 SCV002657735 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-31 criteria provided, single submitter clinical testing The p.T203A variant (also known as c.607A>G), located in coding exon 6 of the PMS2 gene, results from an A to G substitution at nucleotide position 607. The threonine at codon 203 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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