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NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs) AND Familial adenomatous polyposis 2

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Jun 9, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000550116.13

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs)]

NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048174.2(MUTYH):c.1272del (p.Tyr425fs)
HGVS:
  • NC_000001.11:g.45331302del
  • NG_008189.1:g.14169del
  • NM_001048171.2:c.1272del
  • NM_001048172.2:c.1275del
  • NM_001048173.2:c.1272del
  • NM_001048174.2:c.1272delMANE SELECT
  • NM_001128425.2:c.1356del
  • NM_001293190.2:c.1317del
  • NM_001293191.2:c.1305del
  • NM_001293192.2:c.996del
  • NM_001293195.2:c.1272del
  • NM_001293196.2:c.996del
  • NM_001350650.2:c.927del
  • NM_001350651.2:c.927del
  • NM_012222.3:c.1347del
  • NP_001041636.2:p.Tyr425fs
  • NP_001041637.1:p.Tyr426fs
  • NP_001041638.1:p.Tyr425fs
  • NP_001041639.1:p.Tyr425fs
  • NP_001121897.1:p.Tyr453fs
  • NP_001280119.1:p.Tyr440fs
  • NP_001280120.1:p.Tyr436fs
  • NP_001280121.1:p.Tyr333fs
  • NP_001280124.1:p.Tyr425fs
  • NP_001280125.1:p.Tyr333fs
  • NP_001337579.1:p.Tyr310fs
  • NP_001337580.1:p.Tyr310fs
  • NP_036354.1:p.Tyr450fs
  • LRG_220:g.14169del
  • NC_000001.10:g.45796974del
  • NC_000001.11:g.45331302delT
  • NM_001128425.1:c.1356delA
  • NM_001128425.2:c.1356del
  • NR_146882.2:n.1500del
  • NR_146883.2:n.1349del
Protein change:
Y310fs
Links:
dbSNP: rs1553125243
NCBI 1000 Genomes Browser:
rs1553125243
Molecular consequence:
  • NM_001048171.2:c.1272del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048172.2:c.1275del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048173.2:c.1272del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048174.2:c.1272del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001128425.2:c.1356del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293190.2:c.1317del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293191.2:c.1305del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293192.2:c.996del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293195.2:c.1272del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293196.2:c.996del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350650.2:c.927del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350651.2:c.927del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_012222.3:c.1347del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_146882.2:n.1500del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.1349del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
3

Condition(s)

Name:
Familial adenomatous polyposis 2
Synonyms:
COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; MYH-associated polyposis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000639276Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 3, 2024)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004199403Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 22, 2023)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004832243All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 9, 2024)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004848034Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 26, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown3not providednot provided143475not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Characterization of mutant MUTYH proteins associated with familial colorectal cancer.

Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R.

Gastroenterology. 2008 Aug;135(2):499-507. doi: 10.1053/j.gastro.2008.04.035. Epub 2008 May 7.

PubMed [citation]
PMID:
18534194
PMCID:
PMC2761659

MUTYH-associated polyposis (MAP).

Nielsen M, Morreau H, Vasen HF, Hes FJ.

Crit Rev Oncol Hematol. 2011 Jul;79(1):1-16. doi: 10.1016/j.critrevonc.2010.05.011. Epub 2010 Jul 21. Review.

PubMed [citation]
PMID:
20663686
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000639276.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Tyr453Ilefs*14) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colorectal adenoma (PMID: 17219385). This variant is also known as c.1314delA (p.Val452X). ClinVar contains an entry for this variant (Variation ID: 464690). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV004199403.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004832243.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (4)

Description

This variant deletes 1 nucleotide in exon 14/16 of the MUTYH gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant, described as c.1314delA (p.Val452X), has been reported in an individual affected with colorectal cancer carrying a second variant in trans (PMID: 17219385). This variant has also been reported in an individual affected with advanced cancer (PMID: 28873162) and exocrine pancreatic neoplasms (PMID: 29506128). This variant has not been identified 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown143475not providednot provided3not providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848034.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The p.Tyr453IlefsX14 variant in MUTYH has been reported in the compound heterozygous state in 1 individual with polyposis and colorectal cancer (Croitoru 2007 PMID: 17219385). It has also been identified in heterozygous state in individuals with endometrial and pancreatic cancers (Ring 2016 PMID: 27443514, Lowery 2018 PMID: 29506128). It was absent from large population studies and has been reported as Pathogenic by multiple laboratories in ClinVar (Variation ID 464690). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 453 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MUTYH gene is an established disease mechanism in autosomal recessive 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_Supporting, PM2_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 13, 2025