Submissions for variant NM_000179.3(MSH6):c.2591G>A (p.Gly864Glu)

dbSNP: rs587781306

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129021	SCV000172922	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.G864E variant (also known as c.2591G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2591. The glycine at codon 864 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated loss of MSH6 or MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000557524	SCV000624773	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 864 of the MSH6 protein (p.Gly864Glu). 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: 140829). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Color Diagnostics, LLC DBA Color Health	RCV000129021	SCV000908401	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 864 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 been reported in individuals affected with Lynch syndrome-associated tumors that demonstrated loss of MSH6 or MSH2/MSH6 protein expression via immunohistochemistry analysis (ClinVar SCV000172922.9). 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, National Institutes of Health	RCV003997471	SCV004842726	uncertain significance	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 864 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 been reported in individuals affected with Lynch syndrome-associated tumors that demonstrated loss of MSH6 or MSH2/MSH6 protein expression via immunohistochemistry analysis (ClinVar SCV000172922.9). 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.