Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000781992 | SCV000920449 | uncertain significance | Lynch syndrome | 2018-12-19 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability between 0.05 and 0.95 |
| Ambry Genetics | RCV002325487 | SCV002605603 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-18 | criteria provided, single submitter | clinical testing | The p.I1113S variant (also known as c.3338T>G), located in coding exon 5 of the MSH6 gene, results from a T to G substitution at nucleotide position 3338. The isoleucine at codon 1113 is replaced by serine, an amino acid with dissimilar properties. In one functional study utilizing an in vitro complementation assay using MSH6 deficient nuclear extracts from cells, this alteration was found to have moderate evidence in favor of pathogenicity (Drost M et al. Genet Med, 2020 05;22:847-856). This amino acid position is well 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 | RCV003758938 | SCV004470290 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-22 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1113 of the MSH6 protein (p.Ile1113Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 633494). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). 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. |