Submissions for variant NM_000179.3(MSH6):c.3886A>G (p.Lys1296Glu)

gnomAD frequency: 0.00001  dbSNP: rs575714670

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000477645	SCV000551050	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000561056	SCV000662382	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	criteria provided, single submitter	clinical testing	The p.K1296E variant (also known as c.3886A>G), located in coding exon 9 of the MSH6 gene, results from an A to G substitution at nucleotide position 3886. The lysine at codon 1296 is replaced by glutamic acid, an amino acid with 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	RCV000561056	SCV001356410	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1296 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 2/282052 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	RCV001290552	SCV001478621	uncertain significance	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3886A>G (p.Lys1296Glu) results in a conservative amino acid change located in the DNA mismatch repair protein Mut S, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250668 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.3886A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three 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	RCV000561056	SCV002528082	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477984	SCV004222018	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0000071 (2/282052 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	RCV004000829	SCV004835161	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1296 of the MSH6 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 2/282052 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.