Submissions for variant NM_000179.3(MSH6):c.533G>A (p.Arg178His)

gnomAD frequency: 0.00001  dbSNP: rs786204186

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168249	SCV000218920	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000220140	SCV000276282	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	The p.R178H variant (also known as c.533G>A), located in coding exon 3 of the MSH6 gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly 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.
Counsyl	RCV000411795	SCV000489239	uncertain significance	Lynch syndrome 5	2016-09-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000759151	SCV000565211	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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: 22949379, 25224212)
Color Diagnostics, LLC DBA Color Health	RCV000220140	SCV000685500	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 178 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759151	SCV000888292	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000066 (1/152154 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. To the best of our knowledge, this variant has not been reported as a germline variant in individuals with an MSH6-related disorder in the published literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781571	SCV000919723	uncertain significance	not specified	2018-11-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.533G>A (p.Arg178His) results in a non-conservative amino acid change located in the PWWP domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246216 control chromosomes (gnomAD) . 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.533G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five 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.
Mendelics	RCV000411795	SCV001135789	uncertain significance	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411795	SCV004018898	likely benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003468827	SCV004197588	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995618	SCV004838862	uncertain significance	Lynch syndrome	2023-07-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 178 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355537	SCV001550455	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Arg178His variant was not identified in the literature nor was it identified in the following databases: MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database and the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs786204186) as “With uncertain significance allele”, ClinVar (as uncertain significance by Invitae, Ambry Genetics, Counsyl, and GeneDx), Clinvitae (4x as uncertain significance), Cosmic (1x in endometrial tissue as pathogenic (score 0.80). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The variant was identified with a co-occurring pathogenic BARD1 variant (p.Glu59AlafsX8) in one individual from our laboratory, increasing the likelihood that the p.Arg178His variant does not have clinical significance. The p.Arg178His residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.