Submissions for variant NM_000179.3(MSH6):c.3100C>G (p.Arg1034Gly)

dbSNP: rs587779930

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115399	SCV000149308	uncertain significance	not provided	2014-01-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3100C>G at the cDNA level, p.Arg1034Gly (R1034G) at the protein level, and results in the change of an Arginine to a Glycine (CGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg1034Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider MSH6 Arg1034Gly to be a variant of uncertain significance.
Invitae	RCV000808874	SCV000949003	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-17	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) 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. ClinVar contains an entry for this variant (Variation ID: 127578). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs587779930, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1034 of the MSH6 protein (p.Arg1034Gly).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115399	SCV002046394	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321590	SCV002605957	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.R1034G variant (also known as c.3100C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 3100. The arginine at codon 1034 is replaced by glycine, an amino acid with 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	RCV003997245	SCV004837673	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing