Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565247 | SCV000673962 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-09-30 | criteria provided, single submitter | clinical testing | The p.W1047R variant (also known as c.3139T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 3139. The tryptophan at codon 1047 is replaced by arginine, an amino acid with dissimilar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as a variant of uncertain significance (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000758677 | SCV000887448 | uncertain significance | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MSH6 NM_000179.2:c.3139T>C has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214. |
| Labcorp Genetics |
RCV003593991 | SCV004328065 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-09-19 | 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 expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 485873). 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 tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1047 of the MSH6 protein (p.Trp1047Arg). |