Submissions for variant NM_000179.3(MSH6):c.1637A>G (p.Glu546Gly)

dbSNP: rs373554374

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487153	SCV000566846	uncertain significance	not provided	2015-06-09	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1637A>G at the cDNA level, p.Glu546Gly (E546G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Glu546Gly was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Glu546Gly occurs at a position that is conserved in mammals and is located within the binding site of MSH2 (Kariola 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Glu546Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000582070	SCV000690210	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 546 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 1/251204 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706852	SCV000835926	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582070	SCV001172835	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing	The p.E546G variant (also known as c.1637A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1637. The glutamic acid at codon 546 is replaced by glycine, an amino acid with 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004002289	SCV004841802	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 546 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 1/251204 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.