rs121908381

Positions:

• chr1-45331220-C-A
• chr1-45331220-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001048174.2(MUTYH):​c.1354G>T​(p.Glu452*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,614,088 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (2 hom.)
• Consequence: MUTYH NM_001048174.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19 U:1 O:1
• 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]

ENSG00000288208 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-45331220-C-A is Pathogenic according to our data. Variant chr1-45331220-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5297.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Pathogenic=17}. Variant chr1-45331220-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1354G>T	p.Glu452*	stop_gained	14/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1354G>T	p.Glu452*	stop_gained	14/16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1942G>T		non_coding_transcript_exon_variant	18/21			ENSP00000499896.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152212 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: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251492 Hom.: 1 AF XY: 0.0000589 AC XY: 8 AN XY: 135918

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: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461758 Hom.: 2 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000498 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 2 Pathogenic:10 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Founder variant in the British Indian population -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 18, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 09, 2023	The p.Glu480X variant in MUTYH (also referred to as p.Glu466X in the literature) has been reported in at least 9 homozygotes with MUTYH-associated polyposis and segregated in 2 affected homozygotes from one family (Vogt 2009 PMID: 19732775, Inra 2015 PMID: 25590978). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 5297). This variant has been identified in 0.2% (10/4836) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 480, which is predicted to lead to a truncated or absent protein. In vitro functional studies provide support that the p.Glu480X variant impacts protein activity (Ali 2008 PMID: 18534194). Biallelic loss of function of the MUTYH gene is an established disease mechanism in MUTYH-associated polyposis. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MUTYH-associated polyposis. ACMG/AMP Criteria applied: PVS1, PM3, PP1_Moderate, PM2_Supporting, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 09, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This variant changes 1 nucleotide in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as E466X (c.1396G>T) based on an alternate transcript NM_001048171. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that the truncated mutant protein is expressed at low levels in E. coli and exhibits lack of glycosylase activity and DNA-binding activity (PMID: 18534194). This variant has been reported in over ten homozygous individuals affected with polyposis and/or colorectal cancer (PMID: 12393807, 12853198, 17874208, 19732775, 28533537). This variant has been identified in 13/251492 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The stop gained c.1354G>T (p.Glu452Ter) variant in MUTYH gene has been observed in individual(s) with MUTYH-associated polyposis syndrome (MAP). It is commonly reported in individuals of South Asian ancestry (Sampson, Julian R et al.,2003). Functional studies demonstrate a damaging effect: defective glycosylase and DNA binding activities (Ali et al., 2008). The p.Glu452Ter variant has allele frequency 0.005% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.1354G>T in MUTYH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). This variant is present in population databases (rs121908381, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with MUTYH-associated polyposis syndrome (MAP) (PMID: 12393807, 12853198, 15635083, 17369389, 17874208, 19032956, 19732775). It is commonly reported in individuals of South Asian ancestry (PMID: 12853198). This variant is also known as c.1396G>T (p.Glu466X or E466X). ClinVar contains an entry for this variant (Variation ID: 5297). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 17, 2020	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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2024	The MUTYH c.1438G>T (p.Glu480*) variant causes the premature termination of MUTYH protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 35626031 (2022)), Familial adenomatous polyposis (FAP) (PMID: 30604180 (2019), 28533537 (2016), 15635083 (2005)), MUTYH-associated polyposis (MAP) (PMID: 19732775 (2009), 17874208 (2008), 12853198 (2003)), and colorectal cancer (PMID: 12853198 (2007)). This variant has also been identified in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MUTYH)). The frequency of this variant in the general population, 0.00042 (13/30616 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: defective glycosylase and DNA binding activities (Ali 2008); This variant is associated with the following publications: (PMID: 25590978, 19032956, 26202870, 27194394, 26902849, 23035301, 18534194, 33130102, 32411090, 19732775, 12393807, 12853198, 17369389, 15635083, 17874208, 28533537, 28790112, 28381238, 27631816, 30609409, 30604180) -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2023	This variant changes 1 nucleotide in exon 14 of the MUTYH gene, creating a premature translation stop signal. This variant is also known as E466X (c.1396G>T) based on an alternate transcript NM_001048171. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that the truncated mutant protein is expressed at low levels in E. coli and exhibits lack of glycosylase activity and DNA-binding activity (PMID: 18534194). This variant has been reported in over ten homozygous individuals affected with polyposis and/or colorectal cancer (PMID: 12393807, 12853198, 17874208, 19732775, 28533537). This variant has been identified in 13/251492 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 09, 2024	The p.E480* pathogenic mutation (also known as c.1438G>T), located in coding exon 14 of the MUTYH gene, results from a G to T substitution at nucleotide position 1438. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This mutation was first reported in the literature in the homozygous state in three unrelated individuals with greater than 100 colorectal adenomas (Jones S et al. Hum. Mol. Genet. 2002 Nov;11:2961-7). It has since been observed in multiple individuals with a personal history of polyposis in both a compound heterozygous and homozygous state (Nielsen M et al. Gastroenterology. 2009 Feb;136:471-6; Vogt S et al. Gastroenterology. 2009 Dec;137:1976-85.e1-10; Inra JA et al. Genet. Med. 2015 Oct;17:815-21; Khan N et al. Sci Rep. 2017 May;7:2214), as well as a pediatric patient with a high-grade midline glioma (Kline CN et al. Neuro-oncology. 2016 05;18:752-3). Current data indicates that this alteration is more frequently identified in individuals of Asian Indian descent and has been described as a possible founder mutation in individuals of Indian ancestry (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6; Dolwani S et al. Gut. 2007 Apr;56:593; Sampson J et al. Lancet. 2003 Jul 5;362:39-41; Khan N et al. Sci Rep. 2017 May;7:2214). Furthermore, an in vitro functional study demonstrated that the E480* mutant protein was completely devoid of both glycosylase and DNA-binding activities, both of which are essential for the base excision repair properties of the wild-type MUTYH protein (Ali M et al. Gastroenterology. 2008 Aug;135:499-507). This mutation is also designated as E466X and 1396G>T 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MUTYH p.Glu480* variant has been previously reported in numerous publications in individuals with multiple colorectal adenomas and MUTYH-associated polyposis (MAP; selected publications: Jones 2002, Vogt 2009). This variant leads to a premature stop codon at position 480, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MUTYH gene are an established disease mechanism in MAP. In addition, a functional study demonstrated that this variant led to absent glycosylase and no DNA binding activity (Ali 2008). In summary, based on the above information, this variant is classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 04, 2022

- -

MUTYH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant is also referred to as p .Glu466Ter in the literature. This nonsense variant found in exon 14 of 16 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as compound heterozygous and homozygous change in patients with MUTYH-related disorders (PMID: 12393807, 12853198, 15635083, 17369389, 17874208, 19032956, 19732775). This variant is commonly reported in individuals of South Asian ancestry (PMID: 12853198, 28533537, 17369389). Loss-of-function variation in MUTYH is an established mechanism of disease (PMID: 18534194, 20663686). Functional studies showed that the c.1429G>T (p.Glu477Ter) variant alters the function of the MUTYH protein (PMID: 18534194). The c.1429G>T (p.Glu477Ter) variant is present in the gnomAD population database at a frequency of 0.005% (13/ 251492) in the heterozygous state and a frequency of 0.0003% (1 /251492) in the homozygous state. Based on the available evidence, the c.1429G>T (p.Glu477Ter) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.58
ClinPred		0.78	D
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs121908381; hg19: chr1-45796892;