ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.653G>A (p.Gly218Asp)

gnomAD frequency: 0.00001  dbSNP: rs368043334
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460430 SCV000552047 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-10-04 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 218 of the PMS2 protein (p.Gly218Asp). This variant is present in population databases (rs368043334, gnomAD 0.006%). 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: 135071). 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 RCV000580059 SCV000686224 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-03 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 218 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). 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 been identified in 3/251490 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985912 SCV001134605 uncertain significance not provided 2019-07-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580059 SCV001187564 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-14 criteria provided, single submitter clinical testing The p.G218D variant (also known as c.653G>A), located in coding exon 6 of the PMS2 gene, results from a G to A substitution at nucleotide position 653. The glycine at codon 218 is replaced by aspartic acid, 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 tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002483227 SCV002776287 uncertain significance Lynch syndrome 4; Mismatch repair cancer syndrome 4 2022-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000985912 SCV004167918 uncertain significance not provided 2023-10-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11574484, 24728327)
All of Us Research Program, National Institutes of Health RCV003997357 SCV004839942 uncertain significance Lynch syndrome 2023-09-18 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 218 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). 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 been identified in 3/251490 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.
ITMI RCV000121859 SCV000086061 not provided not specified 2013-09-19 no assertion provided reference population

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