Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000702066 | SCV000830900 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-03-27 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1181 of the MSH6 protein (p.Asp1181Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 18566915, 22495361). This missense change has been observed to co-occur in individuals with a different variant in MSH6 that has been determined to be pathogenic (PMID: 18566915, 22495361), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 578919). 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. 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. |
| All of Us Research Program, |
RCV003999723 | SCV004838277 | uncertain significance | Lynch syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 1181 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 been reported in individuals affected with Lynch syndrome. Some of these individuals also carried the pathogenic c.3647 -1G > A that could explain the observed phenotype (PMID: 22495361). 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. |
| Ambry Genetics | RCV004026579 | SCV005032950 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-26 | criteria provided, single submitter | clinical testing | The p.D1181E variant (also known as c.3543C>A), located in coding exon 6 of the MSH6 gene, results from a C to A substitution at nucleotide position 3543. The aspartic acid at codon 1181 is replaced by glutamic acid, an amino acid with highly 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. |