Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485452 | SCV000567856 | uncertain significance | not provided | 2021-10-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21120944, 17531815, 25503501) |
| Ambry Genetics | RCV000563473 | SCV000662428 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-20 | criteria provided, single submitter | clinical testing | The p.R411W variant (also known as c.1231A>T), located in coding exon 4 of the MSH6 gene, results from an A to T substitution at nucleotide position 1231. The arginine at codon 411 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8). This amino acid position is well 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. |
| Labcorp Genetics |
RCV000629980 | SCV000750936 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 411 of the MSH6 protein (p.Arg411Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 419791). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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. |
| Color Diagnostics, |
RCV000563473 | SCV001349864 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-04 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 411 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least 1 individual affected with breast cancer (PMID: 25503501). This variant has not been identified 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. |
| Baylor Genetics | RCV003470548 | SCV004195744 | uncertain significance | Endometrial carcinoma | 2023-06-06 | criteria provided, single submitter | clinical testing |