Submissions for variant NM_001048174.2(MUTYH):c.1471C>T (p.Arg491Trp)

gnomAD frequency: 0.00001  dbSNP: rs754364718

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167076	SCV000217904	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-27	criteria provided, single submitter	clinical testing	The p.R519W variant (also known as c.1555C>T), located in coding exon 16 of the MUTYH gene, results from a C to T substitution at nucleotide position 1555. The arginine at codon 519 is replaced by tryptophan, an amino acid with dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476705	SCV000545768	uncertain significance	Familial adenomatous polyposis 2	2024-12-17	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 519 of the MUTYH protein (p.Arg519Trp). This variant is present in population databases (rs754364718, 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: 187354). 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	RCV000506869	SCV000601639	uncertain significance	not specified	2017-04-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167076	SCV001351732	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 519 of the MUTYH 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 MUTYH-related disorders in the literature. This variant has been identified in 1/251468 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.
GeneDx	RCV001589042	SCV001826423	uncertain significance	not provided	2023-04-04	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: 26489445, 11092888, 23108399)
Baylor Genetics	RCV000476705	SCV004198806	uncertain significance	Familial adenomatous polyposis 2	2024-03-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000476705	SCV004828443	uncertain significance	Familial adenomatous polyposis 2	2023-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 519 of the MUTYH 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 MUTYH-related disorders in the literature. This variant has been identified in 1/251468 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.