Submissions for variant NM_000179.3(MSH6):c.25A>G (p.Ser9Gly)

gnomAD frequency: 0.00002  dbSNP: rs41294986

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130571	SCV000185443	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-14	criteria provided, single submitter	clinical testing	The p.S9G variant (also known as c.25A>G), located in coding exon 1 of the MSH6 gene, results from an A to G substitution at nucleotide position 25. The serine at codon 9 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000235178	SCV000211334	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 23621914, 21153778, 22949387, 12019211, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV000130571	SCV000537613	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 9 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/244896 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.
Invitae	RCV000475467	SCV000551236	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527050	SCV001737882	uncertain significance	not specified	2021-06-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.25A>G (p.Ser9Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consistently, CoDP, a bioinformatics tool to predict the impact of missense variants in MSH6 gene, predicted this variant among those with no functional impact (Terui_2013). The variant allele was found at a frequency of 1.6e-05 in 244896 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.25A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000130571	SCV002535756	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998064	SCV004832220	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 9 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/244896 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.