Submissions for variant NM_000179.3(MSH6):c.2712T>G (p.Asp904Glu)

dbSNP: rs374401174

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115394	SCV000149303	uncertain significance	not provided	2014-01-26	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2712T>G at the cDNA level, p.Asp904Glu (D904E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). This variant has not, to our knowledge, been published in the literature as either a definitive mutation or a benign polymorphism. Terui et al. (2013) published a bioinformatics tool that predicts this variant to have no impact on MSH6 protein. MSH6 Asp904Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one negative polar amino acid for another, altering a position that is well conserved throughout evolution and is located in within domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Asp904Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000535809	SCV000624788	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 904 of the MSH6 protein (p.Asp904Glu). 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: 127573). 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.
Color Diagnostics, LLC DBA Color Health	RCV000583327	SCV000690288	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 904 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.
Ambry Genetics	RCV000583327	SCV001177332	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The p.D904E variant (also known as c.2712T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 2712. The aspartic acid at codon 904 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	RCV003997242	SCV004840739	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 904 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.