ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1675G>A (p.Gly559Arg)

gnomAD frequency: 0.00003  dbSNP: rs751153838
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000471818 SCV000551991 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-12-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV001012607 SCV001173082 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-27 criteria provided, single submitter clinical testing The p.G559R variant (also known as c.1675G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1675. The glycine at codon 559 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in a cohort of 8085 Chinese breast cancer patients (Hu L et al. NPJ Breast Cancer, 2022 Apr;8:52). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV001012607 SCV001343150 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-21 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 559 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 4/251274 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.
GeneDx RCV003227761 SCV003924627 uncertain significance not provided 2023-03-28 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
All of Us Research Program, National Institutes of Health RCV004001876 SCV004844160 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 559 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 4/251274 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 RCV003227761 SCV005625883 uncertain significance not provided 2024-03-15 criteria provided, single submitter clinical testing The PMS2 c.1675G>A (p.Gly559Arg) variant has been reported in the published literature in an individual with breast cancer (PMID: 35449176 (2022)) and in an individual with pancreatic cancer (PMID: 36896836 (2023)). The frequency of this variant in the general population, 0.000016 (4/251274 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics RCV005033990 SCV005668455 uncertain significance Lynch syndrome 4; Mismatch repair cancer syndrome 4 2024-02-22 criteria provided, single submitter clinical testing

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