rs587778536

Positions:

• chr1-45331699-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.1063del​(p.Ala357ProfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: MUTYH NM_001048174.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 O:2
• Conservation: PhyloP100: 0.00100

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-45331699-AG-A is Pathogenic according to our data. Variant chr1-45331699-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45331699-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr1-45331699-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUTYH	NM_001128425.2	c.1147del	p.Ala385ProfsTer23	frameshift_variant	12/16	ENST00000710952.2	NP_001121897.1
MUTYH	NM_001048174.2	c.1063del	p.Ala357ProfsTer23	frameshift_variant	12/16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000710952.2	c.1147del	p.Ala385ProfsTer23	frameshift_variant	12/16		NM_001128425.2	ENSP00000518552
MUTYH	ENST00000456914.7	c.1063del	p.Ala357ProfsTer23	frameshift_variant	12/16	1	NM_001048174.2	ENSP00000407590	A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152238 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: 0.00

GnomAD3 exomes AF: 0.0000640 AC: 16 AN: 249932 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461752 Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

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: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19732775, 23507534, 23007840, 12606733, 31575519, 16557584, 22865608, 24691292, 18534194, 19032956, 20924129, 24728327, 27194394, 23108399, 20618354, 23561487, 28944238, 31589614, 34426522, 26556299, 31921681, 33827469, 30291343, 32088803, 33326660, 30787465, 33077847, 33134171, 30953464, 27829682) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 08, 2021	DNA sequence analysis of the MUTYH gene demonstrated a single base pair deletion in exon 12, c.1147del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 23 amino acids downstream of the change, p.Ala385Profs*23. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated MUTYH protein with potentially abnormal function. Experimental studies have demonstrated that this sequence change impacts the function of the MUTYH protein (18534194, 15987719, 23108399). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the Latino/admixed American subpopulation (dbSNP rs587778536). This pathogenic sequence change is a well-described pathogenic variant identified in multiple individuals in the homozygous and compound heterozygous state with MUTYH-associated polyposis (PMID: 19732775, 26556299, 27829682, 31921681, 28944238, 30291343, 12606733, 32088803, 30953464, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487). Based on these collective evidences, this sequence change is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial adenomatous polyposis 2 Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Ala385Profs*23) 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 (rs587778536, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with multiple colorectal adenomas (PMID: 12606733, 19732775, 23108399, 23561487). This variant is also known as c.1103delC and c.1145delC. ClinVar contains an entry for this variant (Variation ID: 134860). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Common in northern European populations -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 12, 2017	Variant summary: The MUTYH c.1147delC (p.Ala385ProfsX23) 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 pathogenic by our laboratory (e.g., c.1227_1228dupGG [p.Glu410fsX43] and c.1435G>T [p.Glu479X]). MutationTaster predicts a damaging outcome for this variant. This variant was found in 9/119682 control chromosomes at a frequency of 0.0000752, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUTYH variant (0.0045644). The variant has been identified in numerous MAP patients, including homozygous family members (Vogt_2009). In addition, functional studies show that the variant is completely defective in glycosylase and DNA binding activities (Ali_2008). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 22, 2022	ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 supporting, PM3 very strong -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 04, 2018	The MUTYH c.1105delC (p.Ala371ProfsTer23) variant causes a frameshift, and is predicted to result in premature termination of the protein. Truncating variants in the MUTYH gene are known to be disease-causing. Across five studies as a representation of the available literature, the p.Ala371ProfsTer23 variant was identified in a total of 17 individuals with polyposis including sixteen in a compound heterozygous state and one in a homozygous state (Sieber et al. 2003; Nielsen et al. 2005; Aretz et al. 2006; Middeldorp et al. 2008; Laarabi et al. 2012). The variant was absent from 223 control subjects and is reported at a frequency of 0.001212 in the European American population of the Exome Sequencing Project. Functional studies demonstrate that the p.Ala371ProfsTer23 variant results in a truncated protein expressed at <1% of wild type levels which is completely devoid of glycosylase and DNA binding activities. These results are supported by position of the variant with respect to the domain structure of the protein where the variant is predicted to cause the loss of the catalytic domain of the enzyme (Ali et al. 2008; Ruggierie et al. 2013). Based on the collective evidence, the p.Ala371ProfsTer23 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 11, 2019	The p.Ala385fs variant in MUTYH has been reported in >20 individuals (1 homozygote and >20 compound heterozygotes) with MUTYH-related attenuated familial adenomatous polyposis (FAP) and segregated with disease in >6 affected relatives from 4 families (Nielsen 2009, Vogt 2009, Pin 2013, Torrezan 2013, Ruggieri 2013). It has also been identified in 0.01% (4/35430) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 134860). In vitro functional studies provide some evidence that the p.Ala385fs variant may impact protein function (Pin 2013, Ruggieri 2013). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 385 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Homozygous loss of function of the MUTYH gene is an established disease mechanism in individuals with MUTYH-related attenuated FAP. In summary, this variant meets our criteria to be classified as pathogenic for MUTYH-related attenuated FAP in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant deletes 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1105delC, c.1103delC and c.1063delC in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have found this variant to cause MUTYH protein instability and impaired DNA repair activities in carrier cells and abolished glycosylase and DNA binding activities in vitro (PMID: 15987719, 18534194. 23108399). This variant has been observed in multiple homozygous and biallelic carriers affected with polyposis and/or colorectal cancer (PMID: 12606733, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487, 27829682, 28502729, 35668106) and has been observed to segregate in 5 affected members of one Lynch syndrome family (PMID: 24691292). This variant has also been reported in an individual affected with a paranganglioma (PMID: 33748650). This variant has been identified in 18/281328 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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2021	The c.1147delC pathogenic mutation, located in coding exon 12 of the MUTYH gene, results from a deletion of one nucleotide at nucleotide position 1147, causing a translational frameshift with a predicted alternate stop codon (p.A385Pfs*23). This alteration has been reported in a homozygous and compound heterozygous state in multiple individuals with polyposis and has been described as a European founder mutation (Eliason K et al. J. Med. Genet. 2005 Jan;42:95-6; Nielsen M et al. Gastroent. 2009 Feb;136:471-6; Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ricci MT et al. J. Hum. Genet. 2017 Feb;62:309-315; Seguí N et al. Gut. 2015 Feb;64:355-6; Sieber OM et al. N. Engl. J. Med. 2003 Feb 27;348:791-9, Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54; Vogt S et al. Gastroent. 2009 Dec;137:1976-85.e1-10). Functional studies indicate c.1147delC leads to a protein devoid of glycosylase and DNA binding activity (Ali M et al. Gastroent. 2008 Aug;135:499-507), as well as a 50-100% decrease in MUTYH protein expression levels compared to wild-type levels in a compound heterozygous state (Pin E et al. Int. J. Cancer. 2013 Mar;132:1060-9; Ruggieri V et al. Oncogene. 2013 Sep;32:4500-8). Of note, this alteration is also designated as c.1103delC, c.1105delC, and c.1145delC in published 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 03, 2023	This variant deletes 1 nucleotide in exon 12 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is also known as c.1105delC, c.1103delC and c.1063delC in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have found this variant to cause MUTYH protein instability and impaired DNA repair activities in carrier cells and abolished glycosylase and DNA binding activities in vitro (PMID: 15987719, 18534194. 23108399). This variant has been observed in multiple homozygous and biallelic carriers affected with polyposis and/or colorectal cancer (PMID: 12606733, 15635083, 16140997, 16557584, 17368238, 22266422, 22865608, 23561487, 27829682, 28502729, 35668106) and has been observed to segregate in 5 affected members of one Lynch syndrome family (PMID: 24691292). This variant has also been reported in an individual affected with a paranganglioma (PMID: 33748650). This variant has been identified in 18/281328 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. -

Carcinoma of colon Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MUTYH p.Ala385Profsx23 deletion variant was identified in 51 of 1892 proband chromosomes (frequency: 0.027) from individuals or families with adenomatous polyposis or colon cancer (Aretz 2006, Nielsen 2009, Ruggieri 2013, Sieber 2003, Vogt 2009). Of these probands, two individuals were homozygous for the variant and the remaining individuals were compound heterozygotes, harbouring a second MUTYH variant. The variant was previously identified by our laboratory in three individuals with adenomatous polyposis. The variant was also identified in HGMD, the “InSiGHT Colon Cancer Database”, and the ClinVar database (submitted by Inova Translational Medicine Institute, clinical significance not provided). The p.Ala385Profsx23 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 385 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the MUTYH gene are an established mechanism of disease in MUTYH-associated polyposis. In addition, a cell line with the variant showed decreased levels of transcript and protein (Ruggieri 2013), and an in vitro study found that the variant protein had a lower molecular weight than wild-type protein and was devoid of glycosylase and DNA binding activities (Ali 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -

Familial colorectal cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

MUTYH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 09, 2023

The MUTYH c.1147delC variant is predicted to result in a frameshift and premature protein termination (p.Ala385Profs*23). This is a well-documented recurrent variant among Europeans (Seguí et al. 2015. PubMed ID: 24691292) and has also been reported as c.1103delC in the literature among patients with MUTYH-associated polyposis (MAP), multiple colorectal adenomas and familial colorectal cancers (Sieber et al. 2003. PubMed ID: 12606733; Ali et al. 2008. PubMed ID: 18534194; Table S1, Vogt et al. 2009. PubMed ID: 19732775). In addition, in vitro functional studies have shown that this variant has reduced DNA binding activity (Ali et al. 2008. PubMed ID: 18534194), significantly affects protein stability (Parker et al. 2005 PubMed ID: 15987719), and also imposes oxidative stress, thus genetic instability (Ruggieri et al. 2013. PubMed ID: 23108399). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-45797371-AG-A). In ClinVar this variant is interpreted as pathogenic by the vast majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/134860/). Frameshift variants in MUTYH are expected to be pathogenic. This variant is interpreted as pathogenic. -

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)		0.010		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: rs587778536; hg19: chr1-45797371;