Submissions for variant NM_001048174.2(MUTYH):c.14G>A (p.Arg5Gln)

gnomAD frequency: 0.00003  dbSNP: rs587780081

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212697	SCV000149661	uncertain significance	not provided	2023-03-27	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: 21777424, 22297469, 25980754, 26689913, 23108399, 35264596)
Ambry Genetics	RCV000115752	SCV000186396	likely benign	Hereditary cancer-predisposing syndrome	2024-02-07	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	RCV000230254	SCV000285958	uncertain significance	Familial adenomatous polyposis 2	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 19 of the MUTYH protein (p.Arg19Gln). This variant is present in population databases (rs587780081, gnomAD 0.005%). This missense change has been observed in individual(s) with breast cancer, suspected of Lynch syndrome and undergoing MUTYH-associated polyposis testing (PMID: 21777424, 22297469, 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 127834). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine 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.
Counsyl	RCV000230254	SCV000790004	uncertain significance	Familial adenomatous polyposis 2	2017-03-14	criteria provided, single submitter	clinical testing
Mendelics	RCV000230254	SCV000837785	uncertain significance	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115752	SCV000911086	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 19 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 been reported in two individuals affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 21777424) and in an individual affected with breast cancer (PMID: 22297469). This variant has been identified in 7/251490 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	RCV001194162	SCV001363472	uncertain significance	not specified	2019-12-31	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.56G>A (p.Arg19Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.56G>A has been reported in the literature in at-least one individual undergoing clinical genetic testing for Lynch syndrome (Yurgelun_2015) and at-least one individual with breast cancer (Out_2012). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-associated Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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.
Sema4, Sema4	RCV000115752	SCV002532299	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001194162	SCV004025112	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000230254	SCV004835726	uncertain significance	Familial adenomatous polyposis 2	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 19 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 been reported in two individuals affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 21777424) and in an individual affected with breast cancer (PMID: 22297469). This variant has been identified in 7/251490 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	RCV000230254	SCV005056053	uncertain significance	Familial adenomatous polyposis 2	2024-02-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115752	SCV005415574	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-16	criteria provided, single submitter	clinical testing	The missense variant NM_001128425.2(MUTYH):c.56G>A (p.Arg19Gln) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg19Gln variant is observed in 6/113,764 (0.0053%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Arg19Gln variant is novel (not in any individuals) in 1kG. The p.Arg19Gln variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Arg19Gln missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The glutamine residue at codon 19 of MUTYH is present in Gorilla and 7 other mammalian species. The nucleotide c.56 in MUTYH is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212697	SCV005622973	uncertain significance	not provided	2023-10-25	criteria provided, single submitter	clinical testing	The MUTYH c.56G>A (p.Arg19Gln) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 35264596 (2022), 34326862 (2021), 22297469 (2012)) and individuals undergoing genetic testing for Lynch syndrome (PMID: 25980754 (2015)) and MUTYH-associated polyposis (MAP) (PMID: 21777424 (2011)). In a large breast cancer association study, this variant was reported in both healthy individuals and those with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.000053 (6/113764 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	RCV005025179	SCV005654828	uncertain significance	Familial adenomatous polyposis 2; Gastric cancer	2024-02-21	criteria provided, single submitter	clinical testing