Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222748 | SCV000276520 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-24 | criteria provided, single submitter | clinical testing | The p.G1218R variant (also known as c.3652G>C), located in coding exon 8 of the MSH6 gene, results from a G to C substitution at nucleotide position 3652. The glycine at codon 1218 is replaced by arginine, an amino acid with dissimilar properties. This alteration was identified in an individual from Denmark suspected of having hereditary nonpolyposis colorectal cancer (HNPCC) whose tumor demonstrated normal expression of at least MLH1, MSH2, and MSH6 on immunohistochemistry (IHC) (Okkels H et al. Appl. Immunohistochem. Mol. Morphol., 2012 Oct;20:470-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the CoDP in silico tool predicts this alteration to likely impair molecular function, with a score of 1.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001301937 | SCV001491122 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-01-15 | 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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1218 of the MSH6 protein (p.Gly1218Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 22495361). ClinVar contains an entry for this variant (Variation ID: 232391). 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 MSH6 protein function. |
| Center for Genomic Medicine, |
RCV002267961 | SCV002552356 | uncertain significance | not specified | 2025-03-04 | criteria provided, single submitter | clinical testing |