Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000528600 | SCV000625369 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-06-24 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 783 of the MSH2 protein (p.His783Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 455556). 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. 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, |
RCV001180548 | SCV001345503 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-06-06 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001180548 | SCV005033612 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-13 | criteria provided, single submitter | clinical testing | The p.H783D variant (also known as c.2347C>G), located in coding exon 14 of the MSH2 gene, results from a C to G substitution at nucleotide position 2347. The histidine at codon 783 is replaced by aspartic acid, an amino acid with similar properties. 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). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218:). 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. |
| Baylor Genetics | RCV004568719 | SCV005053496 | uncertain significance | Lynch syndrome 1 | 2024-01-04 | criteria provided, single submitter | clinical testing |