ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1143_1144dup (p.Glu382fs) (rs587780078)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235187 SCV000149658 pathogenic not provided 2017-01-27 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.1227_1228dupGG at the cDNA level and p.Glu410GlyfsX43 (E410GfsX43) at the protein level. The normal sequence with the bases that are duplicated in brackets is CCTG[dupGG]AGCC. The duplication causes a frameshift, changing a Glutamic Acid to a Glycine at codon 410, and creating a premature stop codon at position 43 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MUTYH c.1227_1228dupGG, previously reported as c.1186_1187insGG and 1187insGG using an alternate transcript, has been reported in both the homozygous and compound heterozygous state in patients with polyposis and/or early-onset colorectal cancer (Venesio 2004, Vogt 2009, Abdelmaksoud-Dammak 2012). We consider MUTYH c.1227_1228dupGG to be pathogenic.
Invitae RCV000191935 SCV000166444 pathogenic MYH-associated polyposis 2020-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu410Glyfs*43) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587780078, ExAC 0.04%). This variant has been observed in individuals affected with polyposis, colorectal cancer, breast cancer, and cervical cancer (PMID: 15188161, 19531215, 19732775, 15366000). This variant is also known as c.1186_1187insGG (p.Glu396GlyfsX43) in the literature. ClinVar contains an entry for this variant (Variation ID: 127831). 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 RCV000115749 SCV000184139 pathogenic Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing The c.1227_1228dupGG pathogenic mutation, located in coding exon 13 of the MUTYH gene, results from a duplication of GG at nucleotide position 1227, causing a translational frameshift with a predicted alternate stop codon (p.E410Gfs*43). This mutation has been reported in individuals with MUTYH-associated polyposis in both the homozygous and compound heterozygous state (Venesio T et al. Gastroenterology. 2004 Jun;126:1681-5; Isidro G et al. Hum. Mutat. 2004 Oct;24:353-4; Nielsen M et al. J. Med. Genet. 2005 Sep;42:e54; Gomez-Fernandez N et al. BMC Med. Genet. 2009 Jun;10:57; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Abdelmaksoud-Dammak R et al. Fam. Cancer. 2012 Sep;11:503-8; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8; Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20; Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315). Of note, this alteration is also designated as c.1186_1187insGG, 1185_1186dupGG, and 1187insGG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000191935 SCV000678199 pathogenic MYH-associated polyposis 2015-10-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115749 SCV000685556 pathogenic Hereditary cancer-predisposing syndrome 2021-02-01 criteria provided, single submitter clinical testing This variant inserts 2 nucleotides in exon 13 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as c.1185_1186dupGG, c.1186_1187insGG and 1187insGG based on a different transcript (NM_001048171.1). This variant has been reported in multiple individuals affected with polyposis and colorectal cancer in homozygous state (PMID: 15366000, 17122612, 19531215, 19732775) or in compound heterozygous state with a known pathogenic variant in the same gene (PMID: 15188161, 22744763). A study of 36 families affected with polyposis has determined this variant to be a founder mutation in the North African population (PMID: 21443744). This variant has been identified in 40/282334 chromosomes (31/35430 Latino chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000191935 SCV000697671 pathogenic MYH-associated polyposis 2016-10-28 criteria provided, single submitter clinical testing Variant summary: The MUTYH c.1227_1228dupGG (p.Glu410Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent MUTYH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as likely pathogenic by our laboratory (e.g.c.1435G>T/p.Glu479X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/120274 control chromosomes at a frequency of 0.0000582, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). This variant has been reported in numerous MAP patients and colorectal cancer patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000191935 SCV000712103 pathogenic MYH-associated polyposis 2016-08-15 criteria provided, single submitter clinical testing The p.Glu410fs variant in MUTYH has been previously reported as heterozygous in 2 individuals with Lynch syndrome and as homozygous or compound heterozygous in 11 individuals with MUTYH-associated polyposis (MAP; Venesio 2004, Vogt 2009, Da mmak 2012, Ruggieri 2013, Yurgelun 2015). It segregated with disease in 2 affect ed individuals from 2 families (Dammak 2012). In vitro functional studies provid e some evidence that the p.Glu410fs variant may impact protein function (Ruggier i 2013). It has been identified in 30/34416 Latino chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs587780078) . Although this variant has been seen in the general population, its frequency i s low enough to be consistent with a recessive carrier frequency. This variant i s predicted to cause a frameshift, which alters the protein?s amino acid sequenc e beginning at position 410 and leads to a premature termination codon 43 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Homozygous loss of function of the MUTYH gene is an established di sease mechanism in individuals with MAP. In summary, this variant meets criteri a to be classified as pathogenic for FAP in an autosomal recessive manner based upon predicted impact to the protein, presence in multiple affected individuals, and functional studies. ACMG/AMP Criteria applied: PVS1, PS4, PP3_supporting (R ichards 2015).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000235187 SCV000859446 pathogenic not provided 2018-01-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235187 SCV000888298 pathogenic not provided 2017-12-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000191935 SCV000915414 likely pathogenic MYH-associated polyposis 2017-04-28 criteria provided, single submitter clinical testing The MUTYH c.1185_1186dupGG (p.Glu396GlyfsTer43) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Glu396GlyfsTer43 variant has been reported in two studies in which it is found in a total of three individuals with MYH-associated polyposis, including in two in a compound heterozygous state and in one in a heterozygous state (Nielson et al. 2005; LeJeune et al. 2006). The p.Glu396GlyfsTer43 variant was absent from 50 controls and is reported at a frequency of 0.00043 in the Latino population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Glu396GlyfsTer43 variant is classified as likely pathogenic for MYH-associated polyposis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000191935 SCV000025803 pathogenic MYH-associated polyposis 2005-04-15 no assertion criteria provided literature only
Pathway Genomics RCV000144636 SCV000189963 pathogenic Carcinoma of colon 2014-07-24 no assertion criteria provided clinical testing
GeneReviews RCV000191935 SCV000246167 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only

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