Submissions for variant NM_000179.3(MSH6):c.686A>G (p.Glu229Gly)

dbSNP: rs587782591

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131930	SCV000186985	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.E229G variant (also known as c.686A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 686. The glutamic acid at codon 229 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an early onset rectal cancer patient whose tumor showed intact MSH2 and MSH6 staining by immunohistochemistry (IHC) (Limburg PJ et al. Clin. Gastroenterol. Hepatol. 2011 Jun;9:497-502). This alteration was also detected in a colorectal cancer patient whose tumor showed loss of MLH1/PMS2 and intact MSH2/MSH6 staining by IHC where MLH1 promoter hypermethylation was detected (Ambry internal data). 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	RCV000630110	SCV000751066	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-01	criteria provided, single submitter	clinical testing	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: 142618). This missense change has been observed in individual(s) with colorectal cancer (PMID: 21056691). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 229 of the MSH6 protein (p.Glu229Gly).
Color Diagnostics, LLC DBA Color Health	RCV000131930	SCV000908355	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 229 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 been reported in one individual affected with colorectal cancer (PMID: 21056691). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987372	SCV004804337	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.686A>G (p.Glu229Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250610 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.686A>G has been reported in the literature as a VUS in settings of multigene panel testing among individuals affected with colorectal cancer/hereditary cancer (example, Limburg_2011, Li_2020, Bhai_2021). At-least one of these individuals tested positive for MLH1/MSH2/MSH6 by IHC analysis (Limburg_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31391288, 21056691). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998121	SCV004836819	uncertain significance	Lynch syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 229 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 been reported in one individual affected with colorectal cancer (PMID: 21056691). 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.