Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000228587 | SCV000283745 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-06 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 737 of the MSH6 protein (p.Ala737Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 237153). 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 not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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. |
| Ambry Genetics | RCV000490995 | SCV000580365 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-20 | criteria provided, single submitter | clinical testing | The p.A737G variant (also known as c.2210C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2210. The alanine at codon 737 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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. |
| Color Diagnostics, |
RCV000490995 | SCV001341311 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-10 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with glycine at codon 737 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, 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 not been reported in individuals affected with hereditary cancer in the literature. 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 | RCV003463638 | SCV004197613 | uncertain significance | Endometrial carcinoma | 2023-10-19 | criteria provided, single submitter | clinical testing |