ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.254C>T (p.Pro85Leu)

dbSNP: rs1060502945
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467152 SCV000551295 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-02-20 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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 85 of the MSH6 protein (p.Pro85Leu). 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: 410529). 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.
Color Diagnostics, LLC DBA Color Health RCV001181989 SCV001347271 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-01 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 85 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 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.
GeneDx RCV001753899 SCV002007235 uncertain significance not provided 2020-06-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV001181989 SCV002745079 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-05 criteria provided, single submitter clinical testing The p.P85L variant (also known as c.254C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 254. The proline at codon 85 is replaced by leucine, 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.
All of Us Research Program, National Institutes of Health RCV004001858 SCV004828692 uncertain significance Lynch syndrome 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 85 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 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.

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