Submissions for variant NM_001048174.2(MUTYH):c.1516C>T (p.Arg506Trp)

gnomAD frequency: 0.00003  dbSNP: rs144616312

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115763	SCV000149672	uncertain significance	not provided	2024-02-16	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; This variant is associated with the following publications: (PMID: 25340522, 28166811, 11092888, 23108399, 26689913, 33471991)
Ambry Genetics	RCV000220424	SCV000273282	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-25	criteria provided, single submitter	clinical testing	The p.R534W variant (also known as c.1600C>T), located in coding exon 16 of the MUTYH gene, results from a C to T substitution at nucleotide position 1600. The arginine at codon 534 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species, and tryptophan is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475972	SCV000545708	uncertain significance	Familial adenomatous polyposis 2	2025-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 534 of the MUTYH protein (p.Arg534Trp). This variant is present in population databases (rs144616312, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 127842). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115763	SCV000889530	uncertain significance	not provided	2024-01-23	criteria provided, single submitter	clinical testing	The MUTYH c.1600C>T (p.Arg534Trp) variant has been reported in the published literature in individuals affected with glioblastoma (PMID: 26689913 (2015)) and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). This variant has also been identified in at least one reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). The frequency of this variant in the general population, 0.000011 (3/282896 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.
Color Diagnostics, LLC DBA Color Health	RCV000220424	SCV000902907	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 534 of the MUTYH protein. This variant is also known as c.1516C>T (p.Arg506Trp) based on the NM_001048174.2 transcript. 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. In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and 5/53461 controls (OR=1.061, 95%CI 0.324 to 3.477, p-value=1; PMID: 33471991). This variant has also been reported in an individual affected with multiform glioblastoma (PMID: 26689913). This variant has been identified in 3/282896 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.
Sema4, Sema4	RCV000220424	SCV002532260	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465517	SCV002760268	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000475972	SCV004826282	uncertain significance	Familial adenomatous polyposis 2	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 534 of the MUTYH protein. This variant is also known as c.1516C>T (p.Arg506Trp) based on the NM_001048174.2 transcript. 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. In a large international case-control study, this variant was reported in 6/60466 breast cancer cases and 5/53461 controls (OR=1.061, 95%CI 0.324 to 3.477, p-value=1; PMID: 33471991). This variant has also been reported in an individual affected with multiform glioblastoma (PMID: 26689913). This variant has been identified in 3/282896 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.
Baylor Genetics	RCV000475972	SCV005056032	uncertain significance	Familial adenomatous polyposis 2	2024-03-19	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000220424	SCV000805274	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-29	no assertion criteria provided	clinical testing