ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1350GGA[1] (p.Glu452del) (rs587778541)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212719 SCV000149667 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing This pathogenic variant is denoted MUTYH c.1437_1439delGGA at the cDNA level and p.Glu480del (E480del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGGA[delGGA]ATTT. This in frame deletion of three nucleotides results in the loss of a single Glutamic Acid that is located in the Nudix hydrolase domain (Ruggieri 2013, UniProt). MUTYH Glu480del, also denoted as 1395_1397delGGA and 466delE using alternate nomenclature, has been published in the literature as an Italian founder pathogenic variant, and when found in the homozygous state or in combination with another pathogenic MUTYH variant, is known to cause MUTYH-associated polyposis (MAP) (Gismondi 2004, Eliason 2005, Di Gregorio 2006, Vogt 2009, Ricci 2017, de Leon 2017). Multiple in vivo and in vitro functional studies demonstrate the association of MUTYH Glu480del with the defective removal of adenine bases, which is critical to base excision repair (Molatore 2010, D'Agostino 2010, Goto 2010, Ruggieri 2013). We consider this variant to be pathogenic.
Invitae RCV000123145 SCV000166448 pathogenic MYH-associated polyposis 2020-11-01 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 14 of the MUTYH mRNA (c.1437_1439delGGA). This leads to the deletion of 1 amino acid residue in the MUTYH protein (p.Glu480del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587778541, ExAC 0.02%). This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). It has been reported to co-segregate with disease in individuals affected with colorectal cancer, familial adenomatous polyposis (FAP), or attenuated FAP (PMID: 14999774, 15635083, 12707038, 19527492, 16134147, 19732755). This variant is also known as c.1395_1397delGGA, c.1395delGGA, Glu466del, E466del and 452delE in the literature. ClinVar contains an entry for this variant (Variation ID: 127838). Experimental studies have shown that this in-frame deletion disrupts MUTYH protein function (PMID: 23108399, 20848659, 20418187). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115758 SCV000184946 pathogenic Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing The c.1437_1439delGGA pathogenic mutation (also known as p.E480del), located in coding exon 14 of the MUTYH gene, results from a deletion of 3 nucleotides at positions 1437 to 1439, causing the removal of a highly-conserved glutamic acid residue at codon 480. The c.1437_1439delGGA mutation has been reported in conjunction with a second MUTYH mutation in numerous MAP families (Halford SE et al. Am. J. Pathol. 2003 May;162:1545-8; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8; Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315). Functional analysis of this alteration has demonstrated lack of DNA binding capacity and DNA glycosylase activity and an association with defective DNA damage repair following oxidative stress, supporting a pathogenic role in polyp development (Molatore S et al. Hum. Mutat. 2010 Feb;31:159-66; D'Agostino VG et al. DNA Repair (Amst). 2010 Jun;9:700-7; ​Komine K et al. Hum. Mutat. 2015 Jul;36:704-11). Of note, this mutation is also designated as c.1395_1397delGGA and p.E466del in published literature. Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000123145 SCV000271402 pathogenic MYH-associated polyposis 2015-09-14 criteria provided, single submitter clinical testing The p.Glu480del variant in MUTYH (previously reported as p.Glu466del or c.1395_ 1397delGGA) has been reported in more than 15 individuals with MUTYH-associated polyposis either as homozygous or compound heterozygous with another MUTYH varia nt, and segregated with disease in at least 6 affected family members from 3 fam ilies (Halford 2003, Gismondi 2004, Di Gregorio 2006, Vogt 2009, Buisine 2013). This variant is a deletion of the glutamate residue (Glu) at position 480 and is not predicted to alter the protein reading-frame. In vitro functional studies p rovide some evidence that the p.Glu480del variant may impact protein function (D agostino 2010, Goto 2010, Molatore 2010). This variant has also been identified in 10/66728 European and 4/16512 of South Asian chromosomes by the Exome Aggrega tion Consortium, including one homozygote (ExAC, http://exac.broadinstitute.org) . Please note that variants associated with diseases that have reduced penetranc e and late age-of-onset may be present at a low frequency in large population st udies; therefore the frequency of this variant is consistent with the known prev alance and penetrance of this disease. In summary, this variant meets our criter ia to be classified as pathogenic for MUTYH-associated familial polyposis in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM) ba sed upon its frequency in patients, segregation studies, and functional evidence .
Illumina Clinical Services Laboratory,Illumina RCV000123145 SCV000357889 pathogenic MYH-associated polyposis 2016-06-14 criteria provided, single submitter clinical testing The c.1395_1397delGGA (p.Glu466del) variant is an in-frame deletion variant that has been reported extensively in the literature. Across a selection of the available literature, the p.Glu466del variant has been observed in polyposis or colon cancer patients, including in one patient in a homozygous state, eight patients in a compound heterozygous state, and one patient in a heterozygous state (Halford et al. 2003; Gismondi et al. 2004; Peterlongo et al. 2006; DeLellis et al. 2013). The p.Glu466del variant was absent from 1,019 healthy control individuals but is reported at a frequency of 0.00024 in the South Asian population of the Exome Aggregation Consortium. In vitro testing demonstrated that the p.Glu466del variant was dysfunctional in base excision repair and had severely impaired enzymatic activity (Molatore et al. 2010; D'Agostino et al. 2010; Komine et al. 2015). Based on the collective evidence, the p.Glu466del variant is classified as pathogenic for MYH-associated polyposis.
Counsyl RCV000123145 SCV000487331 pathogenic MYH-associated polyposis 2016-01-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212719 SCV000601634 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115758 SCV000685578 pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This variant deletes 3 nucleotides from exon 14 of the MUTYH mRNA, resulting in the in-frame deletion of 1 amino acid from the MUTYH protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies of MUTYH protein function have shown that this variant to be deficient in DNA glycosylase activity and display reduced binding affinity for and repair kinetics toward 8-oxoG (PMID: 19953527, 20418187, 20848659, 23108399, 25820570). This variant has been reported in numerous homozygous and bialleic individuals affected with polyposis and colorectal cancer in the literature (PMID: 12707038, 14999774, 15635083, 16134147, 16557584, 16774938, 16890597, 17031395, 17949294, 19527492, 19793053, 23108399, 23341527, 24278394, 27705013, 27829682). This variant has been identified in 24/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000123145 SCV000778607 pathogenic MYH-associated polyposis 2018-05-08 criteria provided, single submitter research
GeneKor MSA RCV000115758 SCV000821745 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant is an in frame deletion of three base pairs and results in the loss of a single Glutamic Acid in the MUTYH protein. This deletion is located in the Nudix hydrolase domain. This variant, also denoted as 1395_1397delGGA and 466delE using an alternative reference sequence, has been published in the literature as an Italian founder mutation, and, when found in the homozygous state or in combination with another pathogenic MUTYH mutation, is known to cause MUTYH-associated polyposis (MAP) (PMID: 14999774, PMID: 19732775). Multiple in vivo and in vitro functional studies have demonstrated that this variant results in the defective function of the MUTYH protein (PMID: 19953527, PMID: 23108399, PMID: 20848659).
Mendelics RCV000123145 SCV000837745 pathogenic MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123145 SCV000917798 pathogenic MYH-associated polyposis 2020-10-08 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1437_1439delGGA (p.Glu480del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 9.5e-05 in 251478 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in MUTYH causing MUTYH-Associated Polyposis (9.5e-05 vs 0.0046), allowing no conclusion about variant significance. c.1437_1439delGGA has been reported in the literature in many individuals affected with MUTYH-Associated Polyposis (examples- Vogt_2009, Ricci_2016). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples- Goto_2010, Komine_2015). 13 other 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000212719 SCV001251789 pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000212719 SCV001450285 pathogenic not provided 2015-07-09 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000123145 SCV001499747 pathogenic MYH-associated polyposis 2020-04-02 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212719 SCV001762177 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
ITMI RCV000121599 SCV000085796 not provided not specified 2013-09-19 no assertion provided reference population
GeneReviews RCV000123145 SCV000246168 pathogenic MYH-associated polyposis 2019-10-08 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000123145 SCV000592718 pathogenic MYH-associated polyposis no assertion criteria provided clinical testing The MUTYH p.Glu480del variant was identified in 22 of 3686 proband chromosomes (frequency: 0.008) from individuals or families with colorectal cancer, and was not identified in 3404 control chromosomes from healthy individuals (Aceto 2005, Aretz 2006, Colebatch 2006, Eliason 2005, Filipe 2009, Gismondi 2004, DiGregorio 2006, Peterlongo 2006). The variant was also identified in dbSNP (ID: rs587778541) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by Invitae and ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic by GenrDx, Invitae, Ambry Genetics, LMMPHPM, GeneReviews), GeneInsight - COGR database (classified as pathogenic by a clinical laboratory LMM). The variant was also identified by our laboratory in 7 individuals with colorectal cancer. This variant is an in-frame deletion resulting in the removal of a Glutamic acid (Glu) residue at codon 480; the impact of this alteration on MUTYH protein function is not known. This variant is described by Peterlongo (2006) as a known disease causing mutation. In the literature, the variant was found to be prevalent amongst Italian patients, and was frequently compounded with another MUTYH variant, p.Gly396Asp (Aceto 2005, Colebatch 2006, DiGregorio 2006, Eliason 2005, Gismondi 2004). In addition, the variant is located in a conserved structural domain of the MUTYH protein, and in vitro analysis identified severe reduction in the variant protein’s binding affinity towards an 8-oxoG:A DNA substrate as compared to the wild-type protein; this reduced binding was always associated with impairment of glycosylase activity, with adenine removal being totally abrogated (Dagostino 2010, Gismondi 2004, Malatore 2009). 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 RCV001554326 SCV001775495 pathogenic Breast carcinoma 2021-08-09 no assertion criteria provided clinical testing oncocytic carcinoma EST receptor + PRO receptor + HER2 receptor -

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