Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000573144 | SCV000673958 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-11 | criteria provided, single submitter | clinical testing | The p.N742T variant (also known as c.2225A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2225. The asparagine at codon 742 is replaced by threonine, 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 | RCV001340825 | SCV001534654 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-12-13 | 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 MSH6 protein function. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 237154). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with threonine at codon 742 of the MSH6 protein (p.Asn742Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. |
| All of Us Research Program, |
RCV003998716 | SCV004839019 | uncertain significance | Lynch syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with threonine at codon 742 of the MSH6 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 MSH6-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. |