Submissions for variant NM_000179.3(MSH6):c.2033A>G (p.Glu678Gly)

dbSNP: rs1553413404

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580872	SCV000685249	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 678 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). 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.
Invitae	RCV002304216	SCV002592916	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-03	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: 489975). 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 glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 678 of the MSH6 protein (p.Glu678Gly).
Ambry Genetics	RCV000580872	SCV002720229	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The p.E678G variant (also known as c.2033A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2033. The glutamic acid at codon 678 is replaced by glycine, an amino acid with 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004001264	SCV004843746	uncertain significance	Lynch syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 678 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). 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.