Submissions for variant NM_000179.3(MSH6):c.2744C>G (p.Ala915Gly)

dbSNP: rs766427609

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561147	SCV000664871	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	The p.A915G variant (also known as c.2744C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2744. The alanine at codon 915 is replaced by glycine, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590239	SCV000695826	uncertain significance	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2744C>G (p.Ala915Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120742 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000793228	SCV000932571	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 915 of the MSH6 protein (p.Ala915Gly). 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: 480919). 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	RCV000561147	SCV001357878	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000590239	SCV004168056	uncertain significance	not provided	2023-10-27	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: 21120944, 17531815)
Baylor Genetics	RCV003459309	SCV004197709	uncertain significance	Endometrial carcinoma	2023-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000907	SCV004840829	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing