Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000223276 | SCV000276526 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-04-20 | criteria provided, single submitter | clinical testing | The p.V1253I variant (also known as c.3757G>A), located in coding exon 8 of the MSH6 gene, results from a G to A substitution at nucleotide position 3757. The valine at codon 1253 is replaced by isoleucine, an amino acid with highly similar properties. 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. |
| Invitae | RCV000229787 | SCV000283820 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-07-18 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 232396). 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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1253 of the MSH6 protein (p.Val1253Ile). |
| Color Diagnostics, |
RCV000223276 | SCV000685441 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-02 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 1253 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32936981). 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. |
| All of Us Research Program, |
RCV003997971 | SCV004835128 | uncertain significance | Lynch syndrome | 2023-05-23 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with isoleucine at codon 1253 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 32936981). 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. |