Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000160708 | SCV000211338 | uncertain significance | not provided | 2017-12-01 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.97C>T at the cDNA level, p.Arg33Cys (R33C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a liver tumor (Walter 2017). MSH6 Arg33Cys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg33Cys is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg33Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV000490935 | SCV000580233 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-06 | criteria provided, single submitter | clinical testing | The p.R33C variant (also known as c.97C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 97. The arginine at codon 33 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not conserved on limited sequence alignment. 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 | RCV001043688 | SCV001207446 | likely benign | Hereditary nonpolyposis colorectal neoplasms | 2022-12-02 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV003320579 | SCV004024780 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV003998509 | SCV004835551 | uncertain significance | Lynch syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 33 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 MSH6-related disorders in the literature. This variant has been identified in 1/234146 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. |