Submissions for variant NM_001048174.2(MUTYH):c.461G>A (p.Arg154His)

dbSNP: rs143353451

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160752	SCV000211402	pathogenic	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: severely affected glycosylation and suppression of oxidative mutagenesis (Goto et al., 2010; Shinmura et al., 2012; 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: 20848659, 25820570, 17273161, 19032956, 23507534, 30604180, 23322991, 15366000, 14961129, 16890597, 16557584, 19394335, 20618354, 23605219, 21901162, 28452373, 27783336, 29478780, 31589614, 16207212, 35418818, 30291343, 26681312, 32283892, 34704405, 35264596, 28135145, 34758253)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200700	SCV000253867	pathogenic	Familial adenomatous polyposis 2	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 182 of the MUTYH protein (p.Arg182His). This variant is present in population databases (rs143353451, gnomAD 0.002%). This missense change has been observed in individuals with MUTYH-associated polyposis (PMID: 15366000, 16557584, 19032956, 19394335, 20618354). This variant is also known as R154H and R168H. ClinVar contains an entry for this variant (Variation ID: 182689). 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: 20848659, 23322991). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000214896	SCV000273003	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-12	criteria provided, single submitter	clinical testing	The p.R182H pathogenic mutation (also known as c.545G>A), located in coding exon 7 of the MUTYH gene, results from a G to A substitution at nucleotide position 545. The arginine at codon 182 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation has been identified in trans in several individuals with MAP phenotypes (Isidro et al. Hum Mutat 2004 Oct; 24(4):353-4; Di Gregorio et al. Gastroenterology 2006 Aug; 131(2):439-44; Aretz et al. Int J Cancer 2006 Aug 15;119(4): 807-14; Jones N et al. Gastroenterology. 2009 Aug;137(2):489-94, 494.e1; Morak M et al. Clin Genet. 2010 Oct;78(4):353-63). In vitro studies comparing wild-type protein and variant-type proteins demonstrated severely impaired DNA glycosylase activity associated with the p.R182H alelle (Goto et al. Hum Mutat 2010 Nov; 31(11):E1861-74). This alteration has also been reported as functionally defective by one group based on results of a site-directed mutagenesis E. coli study (Komine K et al. Hum. Mutat., 2015 Jul;36:704-11). Of note, this mutation is also designated as p.R168H in published literature. Based on the majority of available evidence to date, this alteration is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508179	SCV000604307	pathogenic	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214896	SCV000685639	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 182 of the MUTYH protein. 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). Functional studies have shown that this variant severely impairs DNA glycosylase activity and ability to suppress mutations (PMID: 20848659, 23322991) and failed to complement a MutY-deficient bacteria strain (PMID: 25820570). This variant has been reported in compound heterozygous state with a pathogenic variant in multiple individuals affected with polyposis and colorectal cancer (PMID: 15366000, 16557584, 19394335, 20618354, 28135145, 29478780, 34704405). This variant has been identified in 3/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occuring at the same position, p.Arg182Cys, is known to be pathogenic (Clinvar variation ID: 187280), indicating that arginine at this position is important for MUTYH protein function. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000200700	SCV000697702	pathogenic	Familial adenomatous polyposis 2	2019-01-29	criteria provided, single submitter	clinical testing	Variant summary: The variant, MUTYH c.545G>A (p.Arg182His) results in a non-conservative amino acid change located in the HhH-GPD domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246268 control chromosomes (gnomAD). The variant, c.545G>A has been reported in the literature in multiple individuals affected with Attenuated familial adenomatous polyposis and colorectal cancer (Morak_2010, Komine_2015, AlDubayan_2018, Yugelun_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Shinmura_2012). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000200700	SCV000837774	pathogenic	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160752	SCV001470576	pathogenic	not provided	2020-06-30	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Other pathogenic or likely pathogenic variants affect the same amino acid . In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
MGZ Medical Genetics Center	RCV000200700	SCV002580600	pathogenic	Familial adenomatous polyposis 2	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478487	SCV002796300	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2022-02-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000200700	SCV004198860	pathogenic	Familial adenomatous polyposis 2	2024-01-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000200700	SCV004837412	pathogenic	Familial adenomatous polyposis 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 182 of the MUTYH protein. 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). Functional studies have shown that this variant severely impairs DNA glycosylase activity and ability to suppress mutations (PMID: 20848659, 23322991) and failed to complement a MutY-deficient bacteria strain (PMID: 25820570). This variant has been reported in compound heterozygous state with a pathogenic variant in multiple individuals affected with polyposis and colorectal cancer (PMID: 15366000, 16557584, 19394335, 20618354, 28135145, 29478780, 34704405). This variant has been identified in 3/251468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occuring at the same position, p.Arg182Cys, is known to be pathogenic (Clinvar variation ID: 187280), indicating that arginine at this position is important for MUTYH protein function. Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000200700	SCV004847558	pathogenic	Familial adenomatous polyposis 2	2019-12-11	criteria provided, single submitter	clinical testing	The p.Arg182His variant in MUTYH has been reported in 6 compound heterozygous individuals with MUTYH-associated attenuated familial adenomatous polyposis (FAP; Isidro 2004, Aretz 2006, Jones 2009, Morak 2010, Marabelli 2016), 2 compound heterozygous individuals with colorectal cancer (CRC; DiGregorio 2006, Morak 2010), 1 heterozygous individual with CRC (Morak 2010), and 2 heterozygous individuals with FAP and/or CRC with no second allele specified (Nielsen 2009, Susswein 2016). This variant has also been reported in ClinVar (Variation ID 182689). This variant has been identified in 0.003% (3/113758) European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg182His variant may impact protein function (Goto 2010, Shinmura 2012). Computational prediction tools and conservation analysis suggest that the p.Arg182His variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2, PP3, PS3_Supporting.
Genomics England Pilot Project, Genomics England	RCV000200700	SCV001760035	pathogenic	Familial adenomatous polyposis 2		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535046	SCV004709136	pathogenic	MUTYH-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The MUTYH c.545G>A variant is predicted to result in the amino acid substitution p.Arg182His. This variant is also known as p.Arg154His, p.Arg168His, and p.Arg179His in the literature. This variant was reported in the homozygous and compound heterozygous states in individuals with autosomal recessive MUTYH-associated polyposis (Isidro et al. 2004. PubMed ID: 15366000; Dell et al. 2021. PubMed ID: 34704405; Ercoskun et al. 2022. PubMed ID: 35418818). This variant was also reported in individuals with neuroblastoma, breast, pancreas, and thyroid cancers (Table S4, Bhai et al. 2021. PubMed ID: 34326862; Table S2, Guindalini et al. 2022. PubMed ID: 35264596; Table S8, Bonfiglio et al. 2023. PubMed ID: 36493725). Functional studies showed that this variant results in reduced DNA glycosylase activity and impaired suppression of oxidative mutagenesis (Goto et al. 2010. PubMed ID: 20848659; Shinmura et al. 2012. PubMed ID: 23322991; Komine et al. 2015. PubMed ID: 25820570). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182689/). A different nucleotide substitution affecting the same amino acid (p.Arg182Cys) has been reported to be causative for autosomal recessive MUTYH-associated polyposis (De Rosa et al. 2009. PubMed ID: 19279422; Komine et al. 2015. PubMed ID: 25820570). Taken together, the c.545G>A (p.Arg182His) variant is interpreted as pathogenic.