Submissions for variant NM_001048174.2(MUTYH):c.1409A>G (p.Gln470Arg)

gnomAD frequency: 0.00001  dbSNP: rs587780085

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212721	SCV000149669	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); 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; This variant is associated with the following publications: (PMID: 16645203, 10612827, 23108399)
Ambry Genetics	RCV000115760	SCV000184342	likely benign	Hereditary cancer-predisposing syndrome	2024-08-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640383	SCV000761974	uncertain significance	Familial adenomatous polyposis 2	2024-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 498 of the MUTYH protein (p.Gln498Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MUTYH-related conditions (PMID: 10612827). This variant is also known as c.1451A>G (p.Gln484Arg). ClinVar contains an entry for this variant (Variation ID: 127840). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000212721	SCV000889524	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing	The MUTYH c.1493A>G (p.Gln498Arg) variant has been reported in the published literature in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). The frequency of this variant in the general population, 0.0000041 (1/242852 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.
Fulgent Genetics, Fulgent Genetics	RCV000765173	SCV000896406	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115760	SCV000903808	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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	RCV000115760	SCV002532247	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	curation
Baylor Genetics	RCV000640383	SCV004198829	uncertain significance	Familial adenomatous polyposis 2	2023-10-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000640383	SCV004832723	uncertain significance	Familial adenomatous polyposis 2	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 498 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has been identified in 1/242852 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115760	SCV005205749	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing