ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1438G>C (p.Gly480Arg)

dbSNP: rs146848345
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129313 SCV000184075 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing The p.G480R variant (also known as c.1438G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1438. The glycine at codon 480 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified once and classified as a variant of unknown significance in a cohort of 105 patients undergoing multi-gene panel testing (Yorczyk A et al, Clin. Genet. 2015 Sep; 88(3):278-82). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Ambry Genetics RCV000216564 SCV000274612 uncertain significance BAP1-related tumor predisposition syndrome 2015-03-24 criteria provided, single submitter clinical testing
GeneDx RCV000589892 SCV000279140 uncertain significance not provided 2023-11-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25318351, 31386297, 28873162)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589892 SCV000697297 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1438G>C (p.Gly480Arg) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant was reported in the literature in a patient being tested for HBOC or Lynch Syndrome, without strong evidence for causality (Yorczyk_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as VUS.
Invitae RCV000629794 SCV000750750 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 480 of the PMS2 protein (p.Gly480Arg). This variant is present in population databases (rs146848345, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or unspecified cancer (PMID: 31386297, 35449176). ClinVar contains an entry for this variant (Variation ID: 141000). 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 with a negative 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.
Color Diagnostics, LLC DBA Color Health RCV000129313 SCV000911857 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 480 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 been reported in a cohort of individuals who met criteria for BRCA1/2 or Lynch syndrome gene testing (PMID: 25318351). This variant has been identified in 2/251486 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.
Fulgent Genetics, Fulgent Genetics RCV002505103 SCV002815788 uncertain significance Lynch syndrome 4; Mismatch repair cancer syndrome 4 2022-03-18 criteria provided, single submitter clinical testing

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