Submissions for variant NM_001048174.2(MUTYH):c.1336C>T (p.Arg446Cys)

gnomAD frequency: 0.00004  dbSNP: rs200229669

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164389	SCV000215025	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-07	criteria provided, single submitter	clinical testing	The p.R474C variant (also known as c.1420C>T), located in coding exon 14 of the MUTYH gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in 1/572 cancer-free atherosclerosis patients (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in two control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This variant was also reported in a cohort study of colorectal patients that also included a control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This variant was identified in the germline along with MUTYH c.603G>T (p.M201I) in a patient in the 80-89 year old age group with colorectal cancer (Georgeson P et al. Nat Commun, 2022 06;13:3254). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000206141	SCV000259566	uncertain significance	Familial adenomatous polyposis 2	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the MUTYH protein (p.Arg474Cys). This variant is present in population databases (rs200229669, gnomAD 0.009%). This missense change has been observed in individual(s) with bilateral breast cancer and colorectal cancer (PMID: 28135145, 32854451). This variant is also known as c.1378C>T (p.Arg460Cys). ClinVar contains an entry for this variant (Variation ID: 41754). 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 disruptive. 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.
GeneDx	RCV000034671	SCV000293927	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing	Observed in individuals with colorectal cancer and breast cancer (Yurgelun 2017, Fanale 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as c.1378C>T, p.R460C; This variant is associated with the following publications: (PMID: 28135145, 23108399, 27535533, 32854451, 22703879, 22722201)
Counsyl	RCV000206141	SCV000487322	uncertain significance	Familial adenomatous polyposis 2	2015-12-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515389	SCV000611406	uncertain significance	Familial adenomatous polyposis 2; Pilomatrixoma; Neoplasm of stomach	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164389	SCV000685574	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034671	SCV000888309	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMID: 28135145 (2017), 28944238 (2017), 35668106 (2022)), and breast cancer (PMID: 32854451 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). This variant has also been reported in unaffected individuals (PMID: 30267214 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MUTYH)). The frequency of this variant in the general population, 0.00026 (3/11610 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 conflicting predictions that this variant is deleterious or 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	RCV000780500	SCV000917805	uncertain significance	not specified	2020-08-03	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) and C-terminal domain (IPR029119) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (5.2e-05 vs 0.0046), allowing no conclusion about variant significance. c.1420C>T has been reported in the literature in individuals affected with atherosclerosis, colorectal cancer and pancreatic ductal adenocarcinoma (Johnston_2012, Yurgelun_2017, Singhi_2019). These reports however, 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. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000206141	SCV004198820	uncertain significance	Familial adenomatous polyposis 2	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000206141	SCV004825680	uncertain significance	Familial adenomatous polyposis 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 474 of the MUTYH protein. This variant is also known as c.1378C>T (p.Arg460Cys) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145, 35668106), bilateral breast cancer (PMID: 32854451) and pancreatic cancer (PMID: 30836094). This variant has also been identified in 14/282888 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.	RCV000164389	SCV005045447	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034671	SCV000043367	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Pathway Genomics	RCV000144638	SCV000189965	uncertain significance	Carcinoma of colon	2014-07-24	no assertion criteria provided	clinical testing