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NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:
May 1, 2023
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:
RCV000235834.30

Allele description [Variation Report for NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp)]

NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp)

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.637C>T (p.Arg213Trp)
HGVS:
  • NC_000001.11:g.45332458G>A
  • NG_008189.1:g.13013C>T
  • NM_001048171.2:c.637C>T
  • NM_001048172.2:c.640C>T
  • NM_001048173.2:c.637C>T
  • NM_001048174.2:c.637C>TMANE SELECT
  • NM_001128425.2:c.721C>T
  • NM_001293190.2:c.682C>T
  • NM_001293191.2:c.670C>T
  • NM_001293192.2:c.361C>T
  • NM_001293195.2:c.637C>T
  • NM_001293196.2:c.361C>T
  • NM_001350650.2:c.292C>T
  • NM_001350651.2:c.292C>T
  • NM_012222.3:c.712C>T
  • NP_001041636.1:p.Arg227Trp
  • NP_001041636.2:p.Arg213Trp
  • NP_001041637.1:p.Arg214Trp
  • NP_001041638.1:p.Arg213Trp
  • NP_001041639.1:p.Arg213Trp
  • NP_001121897.1:p.Arg241Trp
  • NP_001121897.1:p.Arg241Trp
  • NP_001280119.1:p.Arg228Trp
  • NP_001280120.1:p.Arg224Trp
  • NP_001280121.1:p.Arg121Trp
  • NP_001280124.1:p.Arg213Trp
  • NP_001280125.1:p.Arg121Trp
  • NP_001337579.1:p.Arg98Trp
  • NP_001337580.1:p.Arg98Trp
  • NP_036354.1:p.Arg238Trp
  • NP_036354.1:p.Arg238Trp
  • LRG_220t1:c.721C>T
  • LRG_220:g.13013C>T
  • LRG_220p1:p.Arg241Trp
  • NC_000001.10:g.45798130G>A
  • NM_001048171.1:c.679C>T
  • NM_001128425.1:c.721C>T
  • NM_012222.2:c.712C>T
  • NR_146882.2:n.865C>T
  • NR_146883.2:n.714C>T
  • p.R241W
Protein change:
R121W
Links:
dbSNP: rs34126013
NCBI 1000 Genomes Browser:
rs34126013
Molecular consequence:
  • NM_001048171.2:c.637C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.640C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.637C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.637C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.682C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.670C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.637C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.361C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.292C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.292C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.712C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.865C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.714C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
6

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000292738GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Oct 24, 2022)
germlineclinical testing

Citation Link,

SCV000592694Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Pathogenicunknownclinical testing

SCV001134483Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)
Pathogenic
(Sep 4, 2018)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001248084CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(May 1, 2023)
germlineclinical testing

Citation Link,

SCV001450150Clinical Genetics and Genomics, Karolinska University Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jun 16, 2015)
germlineclinical testing

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

SCV001921182Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001958080Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001979882Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus

See additional submitters

no assertion criteria provided
Pathogenicgermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes6not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps.

Guarinos C, Juárez M, Egoavil C, Rodríguez-Soler M, Pérez-Carbonell L, Salas R, Cubiella J, Rodríguez-Moranta F, de-Castro L, Bujanda L, Serradesanferm A, Nicolás-Pérez D, Herráiz M, Fernández-Bañares F, Herreros-de-Tejada A, Aguirre E, Balmaña J, Rincón ML, Pizarro A, Polo-Ortiz F, Castillejo A, Alenda C, et al.

Clin Cancer Res. 2014 Mar 1;20(5):1158-68. doi: 10.1158/1078-0432.CCR-13-1490. Epub 2014 Jan 27.

PubMed [citation]
PMID:
24470512

Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer.

Fleischmann C, Peto J, Cheadle J, Shah B, Sampson J, Houlston RS.

Int J Cancer. 2004 Apr 20;109(4):554-8.

PubMed [citation]
PMID:
14991577
See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000292738.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Published functional studies demonstrate a damaging effect: deficient in glycosylase activity and partially deficient in base excision repair activity (Bai et al., 2005; Komine et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.679C>T p.(Arg227Trp); This variant is associated with the following publications: (PMID: 15366000, 15673720, 19506731, 28127763, 30604180, 32923906, 17931073, 25820570, 21171015, 14991577, 27194394, 27799157, 20663686, 23605219, 23507534, 24470512, 28533537, 28152038, 32338768, 33258288, 30787465, 30613976, 23108399, 11801590, 34704405, 23561487)

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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592694.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The MUTYH p.Arg241Trp variant was identified in 2 of 822 proband chromosomes from individuals with colorectal adenomas (Isidro 2004, Fleischmann 2004). In both cases the variant occurred as a biallelic mutation in combination with the pathogenic MUTYH p.Gly382Asp mutation. The p.Arg241Trp variant was also identified in dbSNP (ID: rs34126013), HGMD, UMD (4X as a causal variant), and the “InSiGHT Colon Cancer Database”. The p.Arg241 residue is conserved across mammals and more distantly related organisms and 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg241Trp variant may impact the protein. In addition, one functional study found the variant to be severely defective in A/8-oxoG binding and glycosylase activities, and it failed to complement MutY-deficiency in E.coli (Bai 2005). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134483.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.

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

From CeGaT Center for Human Genetics Tuebingen, SCV001248084.21

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testingnot provided

Description

MUTYH: PM3:Strong, PS3, PM2, PP3

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided4not providednot providednot provided

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450150.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001921182.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958080.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001979882.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024