Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481662 | SCV000568167 | uncertain significance | not provided | 2016-10-17 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.1216T>G at the cDNA level, p.Cys406Gly (C406G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Cys406Gly was not observed in approximately 6,500 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 Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Cys406Gly occurs at a position that is conserved in mammals and is located in MutS domain I and an MSH2 binding site (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Cys406Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000491552 | SCV000580343 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-15 | criteria provided, single submitter | clinical testing | The p.C406G variant (also known as c.1216T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1216. The cysteine at codon 406 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000491552 | SCV000690185 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-10-28 | criteria provided, single submitter | clinical testing | This missense variant replaces cysteine with glycine at codon 406 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 hereditary cancer in the literature. This variant has been identified in 1/251292 chromosomes 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. |
| Labcorp Genetics |
RCV000796619 | SCV000936139 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2024-09-02 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003464004 | SCV004197718 | uncertain significance | Endometrial carcinoma | 2023-09-19 | criteria provided, single submitter | clinical testing |