ClinVar Miner

Submissions for variant NM_012222.2(MUTYH):c.725G>A (p.Arg242His) (rs140342925)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129105 SCV000183816 pathogenic Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing The p.R245H pathogenic mutation (also known as c.734G>A), located in coding exon 9 of the MUTYH gene, results from a G to A substitution at nucleotide position 734. The arginine at codon 245 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both the homozygous and compound heterozygous state in multiple individuals with personal histories consistent with familial adenomatous polyposis (FAP) or attenuated familial adenomatous polyposis (AFAP) (Aceto G et al. Hum. Mut. 2005 Oct;26:394; Russell AM et al. Int. J. Cancer. 2006 Apr;118:1937-40; Piccioli P et al. Clin. Chem. 2006 Apr;52:739-43; Olschwang S et al. Genet. Test. 2007;11:315-20; Jones N et al. Gastroenterology. 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1975-85; Win AK et al. Gastroenterology. 2014 May;146:1208-11.e1-5; Papp J et al. Fam. Cancer. 2016 Jan;15:85-97; Kacerovska D et al. Am. J. Dermatopathol. 2016 Dec;38:915-92; Yanus GA et al. Clin. Genet. 2018 May;93:1015-1021). Functional studies have shown that the p.R245H mutation, which exists in the highly conserved and catalytic domain of MUTYH, results in severely defective glycosylase activity, severely defective DNA binding activity, and protein expression levels roughly half of that compared to wild-type (Ali M et al. Gastroenterology. 2008 Aug;135:499–507; Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this alteration is also designated as p.R231H (c.692G>A) in published literature. Based on the available evidence to date, this alteration is classified as a pathogenic mutation.
GeneDx RCV000212706 SCV000211405 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.734G>A at the cDNA level, p.Arg245His (R245H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant, also known as MUTYH Arg231His using an alternative reference sequence (NM_001048171.1), has been observed in the compound heterozygous or homozygous state in numerous individuals with a history of polyps and/or colon cancer (Aceto 2005, Piccioli 2006, Olschwang 2007, Russell 2006, Vogt 2009, Win 2014, Papp 2016, Viel 2017, Ricci 2017). Functional studies have shown that this variant results in decreased MUTYH protein expression, impaired glycosylase activity, and an increase in spontaneous mutation events (Ali 2008, Ruggieri 2013, Grasso 2014. Komine 2015). MUTYH Arg245His was observed at an allele frequency of 0.03% (5/18,840 alleles) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FeS cluster (Ruggieri 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, we consider MUTYH Arg245His to be pathogenic.
Invitae RCV000196778 SCV000253868 pathogenic MYH-associated polyposis 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 245 of the MUTYH protein (p.Arg245His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140342925, ExAC 0.02%). This variant has been reported as homozygous or as compound heterozygous in several individuals affected with familial adenomatous polyposis and colorectal cancer (PMID: 16134147, 19732775, 23108399, 24444654, 26446593, 16557584). This variant is also known as c.692G>A (p.Arg231His) in the literature. ClinVar contains an entry for this variant (Variation ID: 140877). Experimental studies have shown that this variant severely affects several aspects of MUTYH protein function (PMID: 18534194, 17081686, 23108399, 24569162, 25820570). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000196778 SCV000487344 likely pathogenic MYH-associated polyposis 2016-03-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129105 SCV000537663 pathogenic Hereditary cancer-predisposing syndrome 2020-08-24 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 245 of the MUTYH protein. This variant is also known by an alternative transcript, NM_001048171, as c.692G>A (p.Arg231His). A different variant affecting the same codon, c.733C>T (p.Arg245Cys), is considered to be disease-causing (ClinVar variation ID: 41761). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies found this variant to be defective in glycosylase assays (PMID: 18534194, 23108399) and caused abnormal increase in DNA 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and mutation frequency (PMID: 23108399, 24569162). This variant has been reported in multiple individuals who are heterozygous and homozygous carriers and affected with polyposis and colorectal cancer (PMID: 16134147,19394335, 19732775, 23108399, 25590978, 29406563, 29967336). This variant has been identified in 24/281670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212706 SCV000601660 pathogenic not provided 2016-10-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515198 SCV000611287 pathogenic MYH-associated polyposis; Pilomatrixoma; Neoplasm of stomach 2017-05-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129105 SCV000821746 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant is a missense mutation replacing Arginine with Histidine in the position 245 of the MUTYH protein. This particular Arginine is highly conserved and located in a functional domain of the protein (FeS cluster domain). However there is no significant physicochemical difference between Arginine and Histidine (Grantham Score 29). The aforementioned variant has been described in literature both in homozygosity and heterozygosity in patients with MUTYH-associated polyposis (PMID: 17949294 , PMID: 16287072, PMID: 16134147). Furthermore published functional studies have shown that the variant affects MUTYH protein functionality (PMID: 18534194, PMID: 23108399).This mutation is present at low frequency in population databases (rs140342925, 0.01%). The mutation database ClinVar contains an entry for this variant (Variation ID: 140877).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000196778 SCV000919794 pathogenic MYH-associated polyposis 2017-09-07 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.734G>A (p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide located in the DNA glycosylase domain and the Helix-turn-helix, base-excision DNA repair, C-terminal domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional assays showed the variant to be associated with defective glycosylase and DNA binding activity and concluded that this variant is functionally defective (Ali_2008, Komine_2015).The variant was found in the control population dataset of ExAC in 16/119648 control chromosomes at a frequency of 0.0001337, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MUTYH-associated polyposis patients, in both homozygotes and compound heterozygotes (Aceto_2005, Vogt_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000196778 SCV001368153 pathogenic MYH-associated polyposis 2019-05-27 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262379 SCV001440223 likely pathogenic Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000212706 SCV001449871 pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000196778 SCV001499744 pathogenic MYH-associated polyposis 2020-04-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353906 SCV000592696 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MUTYH p.Arg245His variant was identified in 15 (2 homozygous, remainder were compound heterozygous) of 3360 proband chromosomes (frequency: 0.004) from individuals or families with MUTYH-associated adenomatous polyposis, familial adenomatous polyposis, or Lynch syndrome and was present in 1 of 2440 control chromosomes (frequency: 0.0004) from healthy individuals (Ruggieri 2013, Vogt 2009, Aceto 2005, Russell 2006, Yanus 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs140342925) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and three other submitters; and classified as likely pathogenic by three submitters), COGR, and UMD-LSDB (23x as causal variant; co-occurring with multiple pathogenic MUTYH mutations). The variant was not identified in Cosmic or MutDB. The variant was identified in control databases in 22 of 276400 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was identified in the following populations: East Asian in 5 of 18840 chromosomes (freq: 0.0003), Other in 1 of 6454 chromosomes (freq: 0.0002), European in 15 of 126098 chromosomes (freq: 0.0001), and African in 1 of 23930 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, Finnish, Latino, or South Asian populations. The p.Arg245 residue is conserved across mammals and other organisms and four out of five 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. Multiple studies have demonstrated that the p.Arg245His variant has functionally reduced or abolished DNA binding and glycosylase activity (Ali 2008, Komine 2015, Ruggieri 2013, Grasso 2014). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001262379 SCV001805831 likely pathogenic Breast carcinoma 2021-08-21 no assertion criteria provided clinical testing Invasive Breast Carcinoma EST= + PRO = - HER2 = - KI = 60-70%

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