Submissions for variant NM_000179.3(MSH6):c.668A>G (p.Asn223Ser)

gnomAD frequency: 0.00001  dbSNP: rs587779316

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579865	SCV000685514	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 223 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 been identified in 1/249670 chromosomes 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.
Invitae	RCV000629721	SCV000750677	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs587779316, 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) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 89554). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 223 of the MSH6 protein (p.Asn223Ser).
GeneDx	RCV001775568	SCV002013815	uncertain significance	not provided	2019-12-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23621914)
Ambry Genetics	RCV000579865	SCV002664862	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-13	criteria provided, single submitter	clinical testing	The p.N223S variant (also known as c.668A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 668. The asparagine at codon 223 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV003997101	SCV004836786	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 223 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249670 chromosomes 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500727	SCV000592574	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Asn223Ser variant was identified in one database InSiGHT Colon Cancer Gene Variant Database 2X as an “uncertain” variant. It was not found in any of the following databases: dbSNP, 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, the ClinVar database, GeneInsight VariantWire database, and UMD. It was included in two bioinformatic studies that predicted the impact of missense variants in MSH6. Both studies concluded that the variant has no impact or is neutral (Terui 2013, Ali 2012). The p.Asn223 residue is not conserved in mammals or other vertebrates and the variant amino acid Serine (Ser) is present in zebrafish, increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. One of 5 in-silico splicing software predicts the creation of a 5' splice site, but this information is not very accurate. This variant was found in our laboratory to co-occur in with a known pathogenic variant c.3957dupA, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.