Submissions for variant NM_001048174.2(MUTYH):c.460C>T (p.Arg154Cys)

gnomAD frequency: 0.00002  dbSNP: rs747993448

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166998	SCV000217819	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.R182C pathogenic mutation (also known as c.544C>T), located in coding exon 7 of the MUTYH gene, results from a C to T substitution at nucleotide position 544. The arginine at codon 182 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been previously identified in conjunction with the c.1437_1439del MUTYH mutation in an individual with 100-1000 polyps and with the p.Y179C MUTYH mutation in two unrelated patients with colon cancer and multiple polyps (De Rosa M et al. Dis Colon Rectum. 2009 Feb;52(2):268-74; Wang L et al. Gastroenterology. 2004 Jul;127(1):9-16; Cattaneo F et al. Genet. Med. 2007 Dec;9(12):836-41). Furthermore, this alteration was reportedly determined to be detected in trans with a pathogenic MUTYH mutation in one patient (Universal Mutation Database [available from www.umd.be]). This alteration has also been identified in a monoallelic state in two individuals with colorectal cancer and/or adenomatous polyps, both of whom met Amsterdam criteria (Morak M et al. Eur. J. Cancer. 2011 May;47(7):1046-55; Steinke V et al. Eur. J. Hum. Genet. 2008 May; 16(5):587-92). A functional complementation assay classified this alteration as defective (Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). Of note, this mutation is also designated as p.R168C in published literature. In addition, a different disease causing mutation, p.R182H, has also been described at this same location. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229525	SCV000285955	pathogenic	Familial adenomatous polyposis 2	2024-01-03	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 182 of the MUTYH protein (p.Arg182Cys). This variant is present in population databases (rs747993448, gnomAD 0.0009%). This missense change has been observed in individual(s) with MUTYH-associated adenomatous polyposis and colorectal cancer (PMID: 15236166, 16890597, 18091433, 18301448, 19279422, 21195604). This variant is also known as p.Arg168Cys. ClinVar contains an entry for this variant (Variation ID: 187280). 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. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15236166, 25820570). This variant disrupts the p.Arg182 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15236166, 20848659, 23322991, 25820570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236750	SCV000293495	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective glycolase activity (Komine et al., 2015); 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; This variant is associated with the following publications: (PMID: 17949294, 21777424, 35545820, 18301448, 19506731, 16890597, 18091433, 15236166, 21195604, 19279422, 27829682, 16042573, 30787465, 25525159, 32761968, 34704405, 25820570)
Counsyl	RCV000229525	SCV000678196	likely pathogenic	Familial adenomatous polyposis 2	2016-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166998	SCV001347956	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 182 of the MUTYH protein. This variant is also known as c.502C>T (p.Arg168Cys) in the literature based on a different transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein is unable to complement MutY-deficient bacterial cells (PMID: 25820570). This variant has been reported in individuals affected with multiple adenomatous polyposis in compound heterozygous state with a known pathogenic variant (PMID: 15236166, 16890597, 18091433). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, NM_001128425.2:c.545G>A (p.Arg182His) (a.k.a. NM_001048174.2:c.461G>A (p.Arg154His)) is known to be disease-causing (ClinVar Variation ID: 182689), indicating that arginine at this position is important for MUTYH function. Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000229525	SCV001429582	pathogenic	Familial adenomatous polyposis 2	2018-03-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236750	SCV001447072	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000229525	SCV002017625	pathogenic	Familial adenomatous polyposis 2	2019-02-20	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002272151	SCV002556809	likely pathogenic	Pilomatrixoma	2019-11-15	criteria provided, single submitter	clinical testing	PSx1, PMx1, PPx3
CeGaT Center for Human Genetics Tuebingen	RCV000236750	SCV002821396	likely pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MUTYH: PM2, PM3, PS3:Moderate
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000229525	SCV003807710	pathogenic	Familial adenomatous polyposis 2	2022-08-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 very strong, PP1 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000229525	SCV003844393	pathogenic	Familial adenomatous polyposis 2	2023-02-06	criteria provided, single submitter	clinical testing	Variant summary: MUTYH c.544C>T (p.Arg182Cys) results in a non-conservative amino acid change located in the HhH-GPD domain(IPR003265) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251458 control chromosomes (gnomAD). c.544C>T has been reported in the literature in individuals affected with MUTYH-Associated Polyposis and colorectal cancer (e.g. Dell_2021, Di Gregorio_2006, Morak_2010, Wang_2004). These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated that this missense resulted in deficient function in a bacterial complementation assay (Komine_2015). Another variant altering the same amino acid (p.R182H) have been reported in affected individuals, suggesting a critical role for this residue (HGMD). Ten 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000229525	SCV004198875	pathogenic	Familial adenomatous polyposis 2	2024-03-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236750	SCV004243127	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000229525	SCV004806425	likely pathogenic	Familial adenomatous polyposis 2	2024-03-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000229525	SCV004837423	pathogenic	Familial adenomatous polyposis 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 182 of the MUTYH protein. This variant is also known as c.502C>T (p.Arg168Cys) in the literature based on a different transcript (NM_001048171). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the mutant protein is unable to complement MutY-deficient bacterial cells (PMID: 25820570). This variant has been reported in individuals affected with multiple adenomatous polyposis in compound heterozygous state with a known pathogenic variant (PMID: 15236166, 16890597, 18091433). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same amino acid position, NM_001128425.2:c.545G>A (p.Arg182His) (a.k.a. NM_001048174.2:c.461G>A (p.Arg154His)) is known to be disease-causing (ClinVar variation ID: 182689), indicating that arginine at this position is important for MUTYH function. Based on the available evidence, this variant is classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000236750	SCV001554005	pathogenic	not provided		no assertion criteria provided	clinical testing	The MUTYH p.Arg182Cys variant was identified in 5 of 1204 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, and was not identified in 2444 control chromosomes from healthy individuals (Cattaneo 2007, De Rosa 2009, Di Gregorio 2006, Olschwang 2007, Steinke 2008). The variant was also identified in dbSNP (ID: rs747993448) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by Invitae and likely pathogenic by ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by Ambry Genetics and Invitae; classified as likely pathogenic by GenDx) and UMD (2x with a “likely causal” classification). In UMD the variant was identified with a co-occurring pathogenic MUTYH variant (c.494A>G, p.Tyr165Cys) increasing the likelihood that the variant has clinical significance. The p.Arg182 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, the variant was identified in patients as one of the biallelic missense variants along with: c.494A>G, p.Tyr165Cys predicted to severely impair the MUTYH protein function (Cattaneo 2007) and c.1395_97delGGA, p.466delE in a patient with classical polyposis phenotype with recessive inheritance (De Rosa 2009). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153454	SCV003843387	benign	Ovarian cancer	2022-01-01	flagged submission	clinical testing