ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2025G>C (p.Glu675Asp)

gnomAD frequency: 0.00001  dbSNP: rs587779223
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219265 SCV000276605 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing The p.E675D variant (also known as c.2025G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2025. The glutamic acid at codon 675 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000541319 SCV000624716 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 675 of the MSH6 protein (p.Glu675Asp). 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: 89239). 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.
Counsyl RCV000662844 SCV000785704 uncertain significance Lynch syndrome 5 2017-11-07 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000219265 SCV001735073 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-30 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with aspartic acid at codon 675 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 been reported in an individual affected with colorectal cancer (http://www.insight-database.org). 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.
Sema4, Sema4 RCV000219265 SCV002535692 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-07 criteria provided, single submitter curation
GeneDx RCV003151745 SCV003840726 uncertain significance not provided 2023-03-07 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22290698, 23621914, 22949387, 17531815, 21120944)
Myriad Genetics, Inc. RCV000662844 SCV004019050 uncertain significance Lynch syndrome 5 2023-03-29 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV003460667 SCV004195734 uncertain significance Endometrial carcinoma 2023-06-14 criteria provided, single submitter clinical testing

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