ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.674C>G (p.Thr225Arg)

dbSNP: rs1553351576
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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 RCV000563305 SCV000669772 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-13 criteria provided, single submitter clinical testing The p.T225R variant (also known as c.674C>G), located in coding exon 4 of the MSH2 gene, results from a C to G substitution at nucleotide position 674. The threonine at codon 225 is replaced by arginine, an amino acid with similar properties. This variant has been detected as homozygous in an individual with no reported features of MSH2-related constitutional mismatch repair deficiency (CMMRD) (Ambry internal data). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae RCV001040053 SCV001203608 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-06-04 criteria provided, single submitter clinical testing 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. 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 expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 483689). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 225 of the MSH2 protein (p.Thr225Arg).
All of Us Research Program, National Institutes of Health RCV004001037 SCV004817362 uncertain significance Lynch syndrome 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces threonine with arginine at codon 225 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). To our knowledge, functional studies have not been reported for this variant. 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). 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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