Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000215122 | SCV000279264 | uncertain significance | not provided | 2016-10-17 | criteria provided, single submitter | clinical testing | This variant is denoted MSH6 c.2673C>G at the cDNA level, p.Ile891Met (I891M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATC>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile891Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ile891Met occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in MutS domain III (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ile891Met is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV000473265 | SCV000551150 | benign | Hereditary nonpolyposis colorectal neoplasms | 2023-10-15 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV001016279 | SCV001177217 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-26 | criteria provided, single submitter | clinical testing | The p.I891M variant (also known as c.2673C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2673. The isoleucine at codon 891 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly 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. |
All of Us Research Program, |
RCV003998617 | SCV004838460 | uncertain significance | Lynch syndrome | 2023-08-08 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with methionine at codon 891 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 2/250540 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. |