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

dbSNP: rs587778541

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212719	SCV000149667	pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: defective base excision repair (Molatore 2010, D'Agostino 2010, Goto 2010, Ruggieri 2013); In silico analysis supports a deleterious effect on splicing; In-frame deletion of 1 amino acid in a non-repeat region; Also known as 1395_1397delGGA and 466delE; This variant is associated with the following publications: (PMID: 20418187, 28283864, 28873162, 28551381, 23108399, 12707038, 19953527, 19732775, 23341527, 15635083, 27783336, 27194394, 27799157, 20848659, 25820570, 24728327, 27705013, 24113346, 30604180, 31159747, 32283892, 34426522, 31589614, 32338768, 33258288, 30787465, 27829682)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123145	SCV000166448	pathogenic	Familial adenomatous polyposis 2	2024-01-30	criteria provided, single submitter	clinical testing	This variant, c.1437_1439del, results in the deletion of 1 amino acid(s) of the MUTYH protein (p.Glu480del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587778541, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with colorectal cancer, familial adenomatous polyposis (FAP), or attenuated FAP (PMID: 12707038, 14999774, 15635083, 16134147, 19527492, 19732755, 23035301). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1395_1397delGGA, c.1395delGGA, Glu466del, E466del and 452delE. ClinVar contains an entry for this variant (Variation ID: 127838). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MUTYH function (PMID: 20418187, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115758	SCV000184946	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-10	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, Mass General Brigham Personalized Medicine	RCV000123145	SCV000271402	pathogenic	Familial adenomatous polyposis 2	2022-06-23	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 variant, and segregated with disease in at least 6 affected family members from 3 families (Halford 2003 PMID: 12707038, Gismondi 2004 PMID: 14999774, Di Gregorio 2006 PMID: 16890597, Vogt 2009 PMID: 19732775, Buisine 2013 PMID: 23341527). It has also been identified in 0.02% (7/30616) of South Asian chromosomes, including one homozygous observation, by gnomAD (http://gnomad.broadinstitute.org). Please note that variants associated with diseases that have reduced penetrance and late age-of-onset may be present at a low frequency in large population studies; therefore the frequency of this variant is consistent with the known prevalance and penetrance of this disease. It has been reported in ClinVar (Variation ID: 127838). 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 provide some evidence that the p.Glu480del variant may impact protein function (Dagostino 2010, Goto 2010, Molatore 2010). In summary, this variant meets our criteria to be classified as pathogenic for MUTYH-associated familial polyposis in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PVS1_Moderate, PS3_Supporting.
Illumina Laboratory Services, Illumina	RCV000123145	SCV000357889	pathogenic	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	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 Diagnostics, LLC DBA Color Health	RCV000115758	SCV000685578	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This variant deletes 3 nucleotides from exon 14 of the MUTYH gene, resulting in the in-frame deletion of 1 amino acid from the MUTYH protein. Experimental studies of MUTYH protein function have shown 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	Familial adenomatous polyposis 2	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	Familial adenomatous polyposis 2	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000123145	SCV000917798	pathogenic	Familial adenomatous polyposis 2	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 and Genomics, 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	Familial adenomatous polyposis 2	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
Revvity Omics, Revvity	RCV000123145	SCV002017635	pathogenic	Familial adenomatous polyposis 2	2023-07-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212719	SCV002070482	pathogenic	not provided	2019-07-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212719	SCV002496881	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	MUTYH: PM3:Very Strong, PM2, PS3:Moderate, PM4:Supporting
Sema4, Sema4	RCV000115758	SCV002532240	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212719	SCV002552407	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498496	SCV002808777	pathogenic	Familial adenomatous polyposis 2; Gastric cancer	2021-07-27	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000123145	SCV004015246	pathogenic	Familial adenomatous polyposis 2	2023-07-07	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 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) with 21 submissions all of which describe it as pathogenic, two stars, no conflicts. Experimental studies have shown that this in-frame deletion disrupts MUTYH protein function (PMID: 23108399, 20848659, 20418187). Therefore, this variant has been classified as pathogenic.
Baylor Genetics	RCV000123145	SCV004198830	pathogenic	Familial adenomatous polyposis 2	2024-03-17	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000123145	SCV004239096	pathogenic	Familial adenomatous polyposis 2	2023-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123145	SCV004829751	pathogenic	Familial adenomatous polyposis 2	2023-12-18	criteria provided, single submitter	clinical testing	The c.1437_1439del (p.Glu480del) variant in the MUTYH gene, located on the exon 17 of the MUTYH gene, results in an in-frame deletion of 1 amino acid of the MUTYH protein. This variant has been reported in homozygous and bialleic state in numerous individuals 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 was also referred as E466del (c.1395_1397del; p.Glu466del) in literature. Experimental studies have shown that this variant causes impaired MUTYH protein function (PMID: 19953527, 20418187, 20848659, 23108399, 25820570). This missense change has been identified in 24/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD), with 1 individual being homozygous. Based on these evidence, the c.1437_1439del (p.Glu480del) variant in the MUTYH gene is classified as pathogenic.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115758	SCV005045340	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000123145	SCV005374476	pathogenic	Familial adenomatous polyposis 2	2024-09-22	criteria provided, single submitter	clinical testing
ITMI	RCV000121599	SCV000085796	not provided	not specified	2013-09-19	no assertion provided	reference population
GeneReviews	RCV000123145	SCV000246168	not provided	Familial adenomatous polyposis 2		no assertion provided	literature only	Common in the Italian population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000123145	SCV000592718	pathogenic	Familial adenomatous polyposis 2		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 -
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001610395	SCV001832544	pathogenic	Colorectal polyposis	2021-09-04	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000212719	SCV001922820	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212719	SCV001963045	pathogenic	not provided		no assertion criteria provided	clinical testing