ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1354G>T (p.Glu452Ter) (rs121908381)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000005618 SCV000153903 pathogenic MYH-associated polyposis 2019-11-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu480*) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908381, ExAC 0.07%). This variant has been observed in individuals affected with MUTYH-associated polyposis syndrome (MAP). It is a frequent disease-causing variant in South Asian individuals with MAP (PMID: 17369389, 12393807, 19732775, 19032956, 12853198, 17874208, 15635083). This variant is also known as c.1396G>T (p.Glu466X or E466X) in the literature. ClinVar contains an entry for this variant (Variation ID: 5297). Experimental studies have shown that this variant leads to reduced expression of a smaller, truncated MUTYH protein that is devoid of both glycosylase and DNA-binding activities (PMID: 18534194). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000222872 SCV000273045 pathogenic Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion)
GeneDx RCV000235388 SCV000293493 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1438G>T at the cDNA level and p.Glu480Ter (E480X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MUTYH Glu480Ter, also reported as Glu466Ter or E466X using alternate nomenclature, is thought to be a founder pathogenic variant in the Indian population and was observed with an allele frequency of 0.05%(15/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant has been observed in the homozygous state in several individuals with colorectal cancer and adenomatous polyposis (Jones 2002, Sampson 2003, Ajith Kumar 2008, Nielsen 2009, Inra 2015, Thomas 2017). Additionally, this variant has been reported in the heterozygous state in at least one individual with colorectal cancer and at least one child with glioblastoma (Dolwani 2007, Kline 2016). An in vitro functional assay demonstrated this variant to have severely defective glycolase and DNA binding activities (Ali 2008). Based on currently available evidence, we consider MUTYH Glu480Ter to be pathogenic.
Counsyl RCV000005618 SCV000487341 pathogenic MYH-associated polyposis 2016-03-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000005618 SCV000592719 pathogenic MYH-associated polyposis 2013-02-05 criteria provided, single submitter clinical testing
Color RCV000222872 SCV000685579 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000005618 SCV000731994 pathogenic MYH-associated polyposis 2017-10-06 criteria provided, single submitter clinical testing The p.Glu480X (NM_001128425.1 c.1438G>T) variant in MUTYH (also referred to as p .Glu466X in the literature) has been reported in at least 9 homozygotes with MUT YH-associated polyposis and segregated in 2 affected homozygotes from one family (Vogt 2009, Inra 2015). It has also been reported in ClinVar (Variation ID#5297 ) as pathogenic by multiple laboratories. This variant has been identified in 15 /30782 of South Asian chromosomes by the Genome Aggregation Database (gnomAD, ht tp://; dbSNP rs121908381). Although this variant has be en seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature t ermination codon at position 480, which is predicted to lead to a truncated or a bsent protein. In vitro functional studies provide support that the p.Glu480X va riant impacts protein activity (Ali 2008). Biallelic loss of function of the MUT YH gene is an established disease mechanism in MUTYH-associated polyposis. In su mmary, this variant meets our criteria to be classified as pathogenic for MUTYH- associated polyposis in an autosomal recessive manner based on observations in a ffected individuals and demonstrated functional impact. ACMG/AMP Criteria applie d: PVS1; PS3; PM2; PM3, PP1, PP5 (Richards 2015).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235388 SCV000889521 pathogenic not provided 2018-07-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000005618 SCV000915413 pathogenic MYH-associated polyposis 2018-08-09 criteria provided, single submitter clinical testing The MUTYH c.1396G>T (p.Glu466Ter) variant, also referred to as p.Glu480Ter, is a stop-gained variant that is predicted to result in premature truncation of the protein. The p.Glu466Ter variant has been reported in at least four studies in which it is found in a homozygous state in 16 individuals with polyposis. Six individuals also developed colorectal cancer with an age of onset ranging between 35 to 65 years (Jones et al. 2002; Vogt et al. 2009; Inra et al. 2015; Khan et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.038835 in the Gujarati Indian in Houston, TX population of the 1000 Genomes Project. Functional data from Ali et al. (2008) showed that the p.Glu466Ter variant protein had dysfunctional glycosylase and DNA binding activity compared with wild type protein. Based on the evidence and potential impact of stop-gained variants, the p.Glu466Ter variant is classified as pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000005618 SCV001134994 pathogenic MYH-associated polyposis 2019-09-18 criteria provided, single submitter clinical testing A homozygous nonsense variation in exon 14 of the MUTYH gene that results in a stop codon and premature truncation of protein at codon 477 was detected. The observed variation has previously been reported in patients and families affected with colorectal cancer (Jones et al. 2002, Sampson et al. 2003) and it lies in the NUDIX domain of the MUTYH_HUMAN protein. An experimental study suggests that the variant results in defective glycosylase and DNA-binding activity. The observed variant c.1429G>T (p.Glu477Ter) has a minor allele frequency of 0.1% and 0.01% in the 1000 genomes and ExAC databases respectively. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the Glu477Ter variant meets our criteria to be classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001174619 SCV001337823 pathogenic MUTYH-associated polyposis 2020-01-17 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1438G>T (p.Glu480X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251492 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is lower than the maximum expected for a pathogenic variant in MUTYH causing MUTYH-associated Polyposis (0.00042 vs 0.0046). The variant (also referred to as p.Glu466X) has been reported in the literature in several homozygous individuals affected with MUTYH-associated Polyposis (e.g. Jones_2009, Vogt_2009), and many of the reported cases were noted to be of Indian ancestry (e.g. Sampson_2003, Dolwani_2007, Inra_2015, Khan_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the truncated protein product had lost its glycosylase- and DNA binding activity (Ali_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000005618 SCV000025800 pathogenic MYH-associated polyposis 2002-11-01 no assertion criteria provided literature only
GeneReviews RCV000005618 SCV000246169 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only

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