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NM_001048174.2(MUTYH):c.1414C>T (p.Gln472Ter) AND Familial adenomatous polyposis 2

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 4, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001202994.8

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1414C>T (p.Gln472Ter)]

NM_001048174.2(MUTYH):c.1414C>T (p.Gln472Ter)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048174.2(MUTYH):c.1414C>T (p.Gln472Ter)
HGVS:
  • NC_000001.11:g.45330536G>A
  • NG_008189.1:g.14935C>T
  • NM_001048171.2:c.1414C>T
  • NM_001048172.2:c.1417C>T
  • NM_001048173.2:c.1414C>T
  • NM_001048174.2:c.1414C>TMANE SELECT
  • NM_001128425.2:c.1498C>T
  • NM_001293190.2:c.1459C>T
  • NM_001293191.2:c.1447C>T
  • NM_001293192.2:c.1138C>T
  • NM_001293195.2:c.1414C>T
  • NM_001293196.2:c.1138C>T
  • NM_001350650.2:c.1069C>T
  • NM_001350651.2:c.1069C>T
  • NM_012222.3:c.1489C>T
  • NP_001041636.2:p.Gln472Ter
  • NP_001041637.1:p.Gln473Ter
  • NP_001041638.1:p.Gln472Ter
  • NP_001041639.1:p.Gln472Ter
  • NP_001121897.1:p.Gln500Ter
  • NP_001280119.1:p.Gln487Ter
  • NP_001280120.1:p.Gln483Ter
  • NP_001280121.1:p.Gln380Ter
  • NP_001280124.1:p.Gln472Ter
  • NP_001280125.1:p.Gln380Ter
  • NP_001337579.1:p.Gln357Ter
  • NP_001337580.1:p.Gln357Ter
  • NP_036354.1:p.Gln497Ter
  • LRG_220t1:c.1498C>T
  • LRG_220:g.14935C>T
  • NC_000001.10:g.45796208G>A
  • NM_001128425.1:c.1498C>T
  • NR_146882.2:n.1642C>T
  • NR_146883.2:n.1491C>T
Protein change:
Q357*
Links:
dbSNP: rs1644624908
NCBI 1000 Genomes Browser:
rs1644624908
Molecular consequence:
  • NR_146882.2:n.1642C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.1491C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001048171.2:c.1414C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001048172.2:c.1417C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001048173.2:c.1414C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001048174.2:c.1414C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001128425.2:c.1498C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001293190.2:c.1459C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001293191.2:c.1447C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001293192.2:c.1138C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001293195.2:c.1414C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001293196.2:c.1138C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001350650.2:c.1069C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001350651.2:c.1069C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_012222.3:c.1489C>T - nonsense - [Sequence Ontology: SO:0001587]

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001374135Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jun 4, 2019) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair.

Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL.

J Biol Chem. 2001 Feb 23;276(8):5547-55. Epub 2000 Nov 22.

PubMed [citation]
PMID:
11092888

Distinct functional consequences of MUTYH variants associated with colorectal cancer: Damaged DNA affinity, glycosylase activity and interaction with PCNA and Hus1.

Brinkmeyer MK, David SS.

DNA Repair (Amst). 2015 Oct;34:39-51. doi: 10.1016/j.dnarep.2015.08.001. Epub 2015 Aug 12.

PubMed [citation]
PMID:
26377631
PMCID:
PMC5098423
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001374135.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change results in a premature translational stop signal in the MUTYH gene (p.Gln500*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acids of the MUTYH protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MUTYH-related conditions. This frameshift disrupts the conserved PCNA binding motif of MUTYH (Gln526-Phe533, also known as Gln512-Phe519 in the literature because of transcript nomenclature differences), which has been shown to be critical for MUTYH-PCNA binding (PMID: 11092888, 26377631). Experimental studies have shown that MUTYH and PCNA co-localize at sites of DNA replication, and that MUTYH-PCNA complexes possess adenine glycosylase activity (PMID: 11433026). In MUTYH-deficient murine cells, a mutated MUTYH protein in which the conserved PCNA binding motif was disrupted did not increase repair efficiency as compared to wild-type MUTYH (PMID: 11864576). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024