Submissions for variant NM_000179.3(MSH6):c.67G>A (p.Ala23Thr)

dbSNP: rs730881810

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212626	SCV000211336	uncertain significance	not provided	2021-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); 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: 28481359, 30609409)
Ambry Genetics	RCV000160706	SCV000215419	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-11	criteria provided, single submitter	clinical testing	The p.A23T variant (also known as c.67G>A), located in coding exon 1 of the MSH6 gene, results from a G to A substitution at nucleotide position 67. The alanine at codon 23 is replaced by threonine, 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.
Invitae	RCV000464022	SCV000551237	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 23 of the MSH6 protein (p.Ala23Thr). 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: 182652). 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	RCV000160706	SCV000903735	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 23 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 hereditary cancer 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780487	SCV000917777	uncertain significance	not specified	2018-10-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.67G>A (p.Ala23Thr) 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. The variant was absent in 269528 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.67G>A 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	RCV000160706	SCV002536345	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998508	SCV004832321	uncertain significance	Lynch syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 23 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 hereditary cancer 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.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249978	SCV001423992	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing