Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000479690 | SCV000567923 | uncertain significance | not provided | 2016-03-22 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.248C>A at the cDNA level, p.Ala83Asp (A83D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala83Asp was not observed in approximately 4,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ala83Asp occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Ala83Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001041899 | SCV001205550 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-04-01 | 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 not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 419824). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 83 of the MSH6 protein (p.Ala83Asp). |
| Ambry Genetics | RCV002431398 | SCV002740469 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-11-24 | criteria provided, single submitter | clinical testing | The p.A83D variant (also known as c.248C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 248. The alanine at codon 83 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is 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. |
| Baylor Genetics | RCV003464002 | SCV004197650 | uncertain significance | Endometrial carcinoma | 2023-10-10 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004002318 | SCV004833271 | uncertain significance | Lynch syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing |