Submissions for variant NM_000179.3(MSH6):c.1735T>G (p.Cys579Gly)

dbSNP: rs1185721664

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001177543	SCV001341770	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 579 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 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.
GeneDx	RCV001776127	SCV002014026	uncertain significance	not provided	2020-07-28	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001875851	SCV002202826	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	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. 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. ClinVar contains an entry for this variant (Variation ID: 919395). 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 cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 579 of the MSH6 protein (p.Cys579Gly).
Ambry Genetics	RCV001177543	SCV002713809	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-27	criteria provided, single submitter	clinical testing	The p.C579G variant (also known as c.1735T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1735. The cysteine at codon 579 is replaced by glycine, an amino acid with highly dissimilar 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.
All of Us Research Program, National Institutes of Health	RCV004006389	SCV004840007	uncertain significance	Lynch syndrome	2023-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 579 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 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.