Submissions for variant NM_000179.3(MSH6):c.2467A>G (p.Ser823Gly)

dbSNP: rs267608032

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213805	SCV000279898	uncertain significance	not provided	2016-02-16	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2467A>G at the cDNA level, p.Ser823Gly (S823G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser823Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser823Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ser823Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854758	SCV002281918	likely benign	Hereditary nonpolyposis colorectal neoplasms	2022-11-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429082	SCV002731683	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-16	criteria provided, single submitter	clinical testing	The p.S823G variant (also known as c.2467A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2467. The serine at codon 823 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003444223	SCV004171376	uncertain significance	Endometrial carcinoma		criteria provided, single submitter	clinical testing	The missense c.2467A>G(p.Ser823Gly) variant in MSH6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as likely benign/ Uncertain significance. The amino acid change p.Ser823Gly in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 823 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance.