Submissions for variant NM_000179.3(MSH6):c.503C>G (p.Ala168Gly)

gnomAD frequency: 0.00001  dbSNP: rs774162322

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164360	SCV000214994	likely benign	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000230583	SCV000283846	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	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 168 of the MSH6 protein (p.Ala168Gly). This variant is present in population databases (rs774162322, gnomAD 0.0009%). 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: 185008). 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.
GeneDx	RCV000657018	SCV000566405	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657018	SCV000601609	uncertain significance	not provided	2022-10-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251426 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in healthy controls (PMID: 33471991 (2021)), see also LOVD ( http://databases.lovd.nl/shared/genes/MSH6)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000485808	SCV000712660	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing	The p.Ala168Gly variant in MSH6 has not been previously reported in individuals with hereditary cancer or in large population studies, but has been identified i n 1/66324 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs774162322). Computational prediction tools and conservation analysis suggest that the p.Ala168Gly variant may not impact the p rotein with several species (fish) carrying the variant amino acid, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala168Gly variant is uncertain.
Counsyl	RCV000662903	SCV000785824	uncertain significance	Lynch syndrome 5	2017-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164360	SCV000911011	likely benign	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150015	SCV003838315	uncertain significance	Breast and/or ovarian cancer	2022-02-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662903	SCV004018887	uncertain significance	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Mayo Clinic Laboratories, Mayo Clinic	RCV000657018	SCV004224909	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	BP4, PM2