Submissions for variant NM_000179.3(MSH6):c.1712G>A (p.Gly571Asp)

dbSNP: rs863224618

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198092	SCV000254278	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 571 of the MSH6 protein (p.Gly571Asp). 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: 216299). 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.
Ambry Genetics	RCV000214529	SCV000275811	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.G571D variant (also known as c.1712G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1712. The glycine at codon 571 is replaced by aspartic acid, 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.
Color Diagnostics, LLC DBA Color Health	RCV000214529	SCV000685218	uncertain significance	Hereditary cancer-predisposing syndrome	2019-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 571 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
GeneDx	RCV001753601	SCV002007306	uncertain significance	not provided	2019-09-19	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV001753601	SCV004704224	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MSH6: PM2, PS4:Moderate, PP3, BP1
Baylor Genetics	RCV004567425	SCV005054851	uncertain significance	Endometrial carcinoma	2024-03-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001753601	SCV005626373	uncertain significance	not provided	2024-08-15	criteria provided, single submitter	clinical testing	The MSH6 c.1712G>A (p.Gly571Asp) variant has been reported in the published literature in an individual with cancer with microsatellite instability (PMID: 31391288 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357770	SCV001553338	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gly571Asp variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs863224618) as With Uncertain significance allele and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Color Genomics) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gly571 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.