Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001019873 | SCV001181285 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | The p.T33R variant (also known as c.98C>G), located in coding exon 1 of the MSH2 gene, results from a C to G substitution at nucleotide position 98. The threonine at codon 33 is replaced by arginine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001055652 | SCV001220052 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-07-06 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with MSH2-related conditions. 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: 823544). 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 33 of the MSH2 protein (p.Thr33Arg). |
| All of Us Research Program, |
RCV004004592 | SCV004828847 | uncertain significance | Lynch syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with arginine at codon 33 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 (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). 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. |