Submissions for variant NM_000179.3(MSH6):c.818G>A (p.Gly273Glu)

dbSNP: rs769610487

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164196	SCV000214817	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	clinical testing	The p.G273E variant (also known as c.818G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 818. The glycine at codon 273 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is not 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.
Invitae	RCV000206680	SCV000260145	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 273 of the MSH6 protein (p.Gly273Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 184864). 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 with a negative predictive value of 95%. 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.
GeneDx	RCV001546884	SCV001766483	uncertain significance	not provided	2020-05-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense 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: 29922827)
All of Us Research Program, National Institutes of Health	RCV003995324	SCV004831495	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 273 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 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356110	SCV001551182	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Gly273Glu variant was not identified in the literature nor was it identified in the COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs769610487) as “With Uncertain significance allele”, ClinVar and Clinvitae databases (2x classified as uncertain significance by Ambry Genetics and Invitae). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Consortium (Feb 27, 2017). The p.Gly273Glu residue is not conserved in mammals and four out of five 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. 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 difference in splicing. The variant is located within the DNA mismatch repair protein Msh6 functional domain. 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.