rs587778541

Positions:

• chr1-45331218-TTCC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The ENST00000456914.7(MUTYH):​c.1353_1355del​(p.Glu452del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E451E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: MUTYH ENST00000456914.7 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33 O:2
• Conservation: PhyloP100: 7.31

Genes affected

MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000456914.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-45331218-TTCC-T is Pathogenic according to our data. Variant chr1-45331218-TTCC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331218-TTCC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1353_1355del	p.Glu452del	inframe_deletion	14/16	ENST00000456914.7	NP_001041639.1
MUTYH	NM_001128425.2	c.1437_1439del	p.Glu480del	inframe_deletion	14/16	ENST00000710952.2	NP_001121897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1353_1355del	p.Glu452del	inframe_deletion	14/16	1	NM_001048174.2	ENSP00000407590	A1
MUTYH	ENST00000710952.2	c.1437_1439del	p.Glu480del	inframe_deletion	14/16		NM_001128425.2	ENSP00000518552

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251478 Hom.: 1 AF XY: 0.000125 AC XY: 17 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461892 Hom.: 1 AF XY: 0.0000591 AC XY: 43 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:15 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	Common in the Italian population -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 08, 2018	- -

not provided Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MUTYH: PM3:Very Strong, PM2, PS3:Moderate, PM4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2023	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 18, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -

Gastric cancer;C3272841:Familial adenomatous polyposis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Breast carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Aug 09, 2021

oncocytic carcinoma EST receptor + PRO receptor + HER2 receptor - -

Colorectal polyposis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 04, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778541; hg19: chr1-45796890;