rs587778536

Variant names:

• chr1-45331699-AG-A
• rs587778536
• NM_001048174.2:c.1063delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001048174.2(MUTYH):​c.1063delC​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. L355L) has been classified as Likely benign. 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:32 O:2
• Conservation: PhyloP100: 0.00100
• Publications: 42 publications found

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]

MUTYH Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• colorectal cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD, AR Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-45331699-AG-A is Pathogenic according to our data. Variant chr1-45331699-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 134860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUTYH	NM_001048174.2	c.1063delC	p.Ala357ProfsTer23	frameshift_variant	Exon 12 of 16	ENST00000456914.7	NP_001041639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUTYH	ENST00000456914.7	c.1063delC	p.Ala357ProfsTer23	frameshift_variant	Exon 12 of 16	1	NM_001048174.2	ENSP00000407590.2
ENSG00000288208	ENST00000671898.1	n.1651delC		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000499896.1

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

GnomAD2 exomes AF: 0.0000640 AC: 16 AN: 249932 AF XY: 0.0000590

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1112008

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

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

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

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:32 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:12

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 26, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MUTYH c.1147del; p.Ala385ProfsTer23 variant (rs587778536), also known as 1105del, is reported in the literature in multiple individuals with MUTYH-associated polyposis (see Nielsen 2005, Sieber 2003, Sommer 2022, Vogt 2009). This variant is also reported in ClinVar (Variation ID: 134860). It is observed in the general population with an overall allele frequency of 0.006% (18/281328 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Nielsen M et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet. 2005 Sep;42(9):e54. PMID: 16140997. Sieber OM et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003 Feb 27;348(9):791-9. PMID: 12606733. Sommer AK et al. Solving the genetic aetiology of hereditary gastrointestinal tumour syndromes- a collaborative multicentre endeavour within the project Solve-RD. Eur J Med Genet. 2022 May;65(5):104475. PMID: 35283344. Vogt S et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009 Dec;137(6):1976-85.e1-10. PMID: 19732775. -

Familial adenomatous polyposis 2 Pathogenic:11 Other:1

Dec 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Sep 12, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 02, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 04, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common in northern European populations -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 06, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 22, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS3 supporting, PM2 supporting, PM3 very strong -

Hereditary cancer-predisposing syndrome Pathogenic:4

Apr 03, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 03, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_VeryStrong, PM3_Strong c.1147del, located in exon 12 of the MUTYH gene, consists in the deletion of one nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(Ala385Profs*23). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1).This variant is found in 16/266828 alleles at a frequency of 0.006% in the gnomAD v2.1.1 database, non-cancer dataset. Multiple affected individuals have been reported with this variant in trans with another pathogenic variant (PM3_strong). This variant has been reported in the ClinVar database (1x likely pathogenic, 25x pathogenic) and in the LOVD database (numerous times as pathogenic and likely pathogenic). Based on currently available information, the variant c.1147del should be considered a pathogenic variant. -

May 30, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Aug 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Segu&iacute; 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. -

Carcinoma of colon Pathogenic:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial colorectal cancer Pathogenic:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MUTYH-related disorder Pathogenic:1

Oct 09, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0010
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587778536; hg19: chr1-45797371; COSMIC: COSV108171665;