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NM_001048174.2(MUTYH):c.49del (p.Ala17fs) AND Familial adenomatous polyposis 2

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Sep 23, 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:
RCV000640397.12

Allele description [Variation Report for NM_001048174.2(MUTYH):c.49del (p.Ala17fs)]

NM_001048174.2(MUTYH):c.49del (p.Ala17fs)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048174.2(MUTYH):c.49del (p.Ala17fs)
HGVS:
  • NC_000001.11:g.45334457del
  • NG_008189.1:g.11014del
  • NM_001048171.2:c.49del
  • NM_001048172.2:c.49del
  • NM_001048173.2:c.49del
  • NM_001048174.2:c.49delMANE SELECT
  • NM_001128425.2:c.91del
  • NM_001293190.2:c.91del
  • NM_001293191.2:c.49del
  • NM_001293192.2:c.-164del
  • NM_001293195.2:c.49del
  • NM_001293196.2:c.-164del
  • NM_001350650.2:c.-223del
  • NM_001350651.2:c.-159del
  • NM_012222.3:c.91del
  • NP_001041636.2:p.Ala17fs
  • NP_001041637.1:p.Ala17fs
  • NP_001041638.1:p.Ala17fs
  • NP_001041639.1:p.Ala17fs
  • NP_001121897.1:p.Ala31fs
  • NP_001280119.1:p.Ala31fs
  • NP_001280120.1:p.Ala17fs
  • NP_001280124.1:p.Ala17fs
  • NP_036354.1:p.Ala31fs
  • LRG_220:g.11014del
  • NC_000001.10:g.45800129del
  • NM_001128425.1:c.91delG
  • NM_001128425.2:c.91del
  • NR_146882.2:n.277del
  • NR_146883.2:n.200del
  • p.A31PFS*27
Protein change:
A17fs
Links:
dbSNP: rs587781704
NCBI 1000 Genomes Browser:
rs587781704
Molecular consequence:
  • NM_001293192.2:c.-164del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001293196.2:c.-164del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001350650.2:c.-223del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001350651.2:c.-159del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001048171.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048172.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048173.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048174.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001128425.2:c.91del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293190.2:c.91del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293191.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293195.2:c.49del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_012222.3:c.91del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_146882.2:n.277del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.200del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

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
SCV000761988Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 1, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001361126Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Oct 15, 2021)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV004198859Baylor Genetics
criteria provided, single submitter

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

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

SCV005429881All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 23, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not 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 (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000761988.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Ala31Profs*27) 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 (rs587781704, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MUTYH-related conditions. ClinVar contains an entry for this variant (Variation ID: 141379). For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361126.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: MUTYH c.91delG (p.Ala31ProfsX27) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251478 control chromosomes. c.91delG has been reported in the literature in multiple individuals affected with MUTYH-Associated Polyposis (Inra_2015). This variant was also identified in an individual with Renal Cancer and the individual was a carrier for this variant (Hartman_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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.

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

From Baylor Genetics, SCV004198859.1

#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, SCV005429881.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This variant deletes 1 nucleotide in exon 2 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 has been identified in 5/251478 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown143475not providednot provided1not providednot providednot provided

Last Updated: Feb 1, 2025