Submissions for variant NM_000179.3(MSH6):c.3586G>C (p.Glu1196Gln)

gnomAD frequency: 0.00001  dbSNP: rs75095286

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467878	SCV000551255	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574327	SCV000662476	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The p.E1196Q variant (also known as c.3586G>C), located in coding exon 7 of the MSH6 gene, results from a G to C substitution at nucleotide position 3586. The glutamic acid at codon 1196 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000574327	SCV000685417	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1196 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 3/282564 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587963	SCV000695876	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3586G>C (p.Glu1196Gln) variant located in the P-loop containing nucleoside triphosphate hydrolase domain (via InterPro) causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121274 (1/60637), predominantly in the African cohort, 2/10370 (1/5185), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037 (0.0001421). The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, due to the limited available information (ie, lack of clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
GeneDx	RCV000587963	SCV001820659	uncertain significance	not provided	2023-04-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Sema4, Sema4	RCV000574327	SCV002528049	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496782	SCV002800128	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-08-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470469	SCV004197740	uncertain significance	Endometrial carcinoma	2023-09-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587963	SCV004221231	uncertain significance	not provided	2023-05-11	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00012 (3/24930 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV004001852	SCV004835097	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1196 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 3/282564 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.