Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216891 | SCV000277360 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | The p.E1090D variant (also known as c.3270G>C), located in coding exon 5 of the MSH6 gene, results from a G to C substitution at nucleotide position 3270. The glutamic acid at codon 1090 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000457746 | SCV000551185 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1090 of the MSH6 protein (p.Glu1090Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 233061). 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 not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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. |
| Mendelics | RCV000708886 | SCV000837913 | uncertain significance | Lynch syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001001136 | SCV001158280 | uncertain significance | not specified | 2019-03-13 | criteria provided, single submitter | clinical testing | The MSH6 c.3270G>C; p.Glu1090Asp variant (rs876660165), to our knowledge, is not described as a germline variant in the medical literature but contains an entry in ClinVar (Variation ID: 233061). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 1090 is moderately conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. However, due to the lack of clinical and functional data regarding this variant, its clinical significance cannot be determined with certainty. |
| Color Diagnostics, |
RCV000216891 | SCV002053419 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-06 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 1090 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer 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. |