Submissions for variant NM_000179.3(MSH6):c.3992G>A (p.Arg1331Gln)

dbSNP: rs184131049

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482748	SCV000568116	uncertain significance	not provided	2023-10-23	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 reported as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 27294619, 22851212, 26991699, 17531815, 21120944, 12019211, 31857677)
Ambry Genetics	RCV000491185	SCV000580208	likely benign	Hereditary cancer-predisposing syndrome	2020-07-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000707566	SCV000836667	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482748	SCV001134450	uncertain significance	not provided	2023-08-12	criteria provided, single submitter	clinical testing	In the published literature, this variant as a somatic variant in a colorectal cancer tumor, with microsatellite instability and discordant immunohistochemical results (PMID: 31857677 (2020)). In the same study, the variant was found to co-occur with a germline pathogenic MSH6 variant (PMID: 31857677 (2020)). The frequency of this variant in the general population, 0.0000041 (1/245650 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000986744	SCV001135856	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491185	SCV001352057	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1331 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 been identified in 1/245650 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	RCV003479136	SCV004222899	uncertain significance	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3992G>A (p.Arg1331Gln) results in a 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 allele was found at a frequency of 4.1e-06 in 245650 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.3992G>A has been reported in the germline of individuals affected with Prostate Cancer or Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as uncertain significance and two classified it as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004541518	SCV004765147	uncertain significance	MSH6-related disorder	2024-02-02	criteria provided, single submitter	clinical testing	The MSH6 c.3992G>A variant is predicted to result in the amino acid substitution p.Arg1331Gln. To our knowledge, this variant has not been reported in the literature as a germline variant. This variant is reported in 0.0063% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/419915/?new_evidence=true). Another missense variant affecting this residue has been associated with colorectal cancer (p.Arg1331Pro; Belvederesi et al. 2012. PubMed ID: 22851212). At this time, the clinical significance of the c.3992G>A variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003312	SCV004835191	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1331 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 been reported in individuals affected with gastric cancer (Universal Mutation Database, PMID: 10612827. This variant has been identified in 1/245650 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.