ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2570A>G (p.Asp857Gly)

dbSNP: rs758176077
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000814142 SCV000954543 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-03-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 857 of the MSH6 protein (p.Asp857Gly). This variant is present in population databases (rs758176077, gnomAD 0.0009%). 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: 657525). This variant has not been reported in the literature in individuals affected with MSH6-related conditions.
Ambry Genetics RCV002424917 SCV002740293 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter clinical testing The p.D857G variant (also known as c.2570A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2570. The aspartic acid at codon 857 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV003315443 SCV004015204 uncertain significance Lynch syndrome 5 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 857 of the MSH6 protein (p.Asp857Gly). This variant is not found in gnomAD genomes. In-silico predictions show pathogenic computational verdict based on 10 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor and MutationTaster vs 2 benign predictions from PrimateAI and SIFT. The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant has not been reported in the literature in individuals with MSH6-related conditions. Therefore, it has been classified as a Variant of Uncertain Significance.

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