ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1954C>A (p.Pro652Thr)

dbSNP: rs876660900
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217856 SCV000278697 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-28 criteria provided, single submitter clinical testing The p.P652T variant (also known as c.1954C>A), located in coding exon 12 of the MSH2 gene, results from a C to A substitution at nucleotide position 1954. The proline at codon 652 is replaced by threonine, an amino acid with highly similar properties. While this exact alteration has not been reported in the literature, an alteration at the same codon, p.P652H (c.1955C>A), has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]).The p.P652T variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Since supporting evidence is limited at this time, the clinical significance of p.P652T remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000818109 SCV000958706 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-11-17 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 652 of the MSH2 protein (p.Pro652Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 234174).
Color Diagnostics, LLC DBA Color Health RCV000217856 SCV004356713 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-11 criteria provided, single submitter clinical testing This missense variant replaces proline with threonine at codon 652 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1955C>A (p.Pro652His), is considered to be disease-causing (ClinVar variation ID: 90823), suggesting that this position is important for the protein function. 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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