ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.408G>A (p.Met136Ile)

gnomAD frequency: 0.00003  dbSNP: rs1064794077
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484071 SCV000567744 uncertain significance not provided 2023-05-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484, 31857677)
Ambry Genetics RCV000563701 SCV000670794 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-08 criteria provided, single submitter clinical testing The p.M136I variant (also known as c.408G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 408. The methionine at codon 136 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. 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.
Invitae RCV000794842 SCV000934274 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 136 of the PMS2 protein (p.Met136Ile). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 419740). 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. 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.
Color Diagnostics, LLC DBA Color Health RCV000563701 SCV004359683 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-05 criteria provided, single submitter clinical testing This missense variant replaces methionine with isoleucine at codon 136 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 3/251142 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.

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