Submissions for variant NM_000179.3(MSH6):c.208A>G (p.Lys70Glu)

gnomAD frequency: 0.00001  dbSNP: rs863224621

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000199329	SCV000254290	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 70 of the MSH6 protein (p.Lys70Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 216304). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000445836	SCV000537594	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 70 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 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.
Ambry Genetics	RCV000445836	SCV000580268	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-29	criteria provided, single submitter	clinical testing	The p.K70E variant (also known as c.208A>G), located in coding exon 1 of the MSH6 gene, results from an A to G substitution at nucleotide position 208. The lysine at codon 70 is replaced by glutamic acid, 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.
GeneDx	RCV001589077	SCV001825804	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Not observed 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
All of Us Research Program, National Institutes of Health	RCV003996997	SCV004828570	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 70 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 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001589077	SCV001956318	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001589077	SCV001974231	likely benign	not provided		no assertion criteria provided	clinical testing