Submissions for variant NM_000179.3(MSH6):c.116G>C (p.Gly39Ala)

dbSNP: rs1042821

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480607	SCV000566644	uncertain significance	not provided	2016-05-16	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.116G>C at the cDNA level, p.Gly39Ala (G39A) at the protein level, and results in the change of a Glycine to an Alanine (GGG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly39Ala 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 Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. MSH6 Gly39Ala occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002, 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 Gly39Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000823347	SCV000964201	benign	Hereditary nonpolyposis colorectal neoplasms	2023-07-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002329143	SCV002631714	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	clinical testing	The p.G39A variant (also known as c.116G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 116. The glycine at codon 39 is replaced by alanine, an amino acid with similar properties. This amino acid position is not 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	RCV004002284	SCV004824519	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 39 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 2/231236 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.