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NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp) AND Familial adenomatous polyposis 2

Germline classification:
Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:
Jan 28, 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:
RCV000369240.22

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:
5

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
SCV000357900Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification 20161018)
Likely pathogenic
(Jun 14, 2016)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000545770Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 28, 2024)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000678194Counsyl
criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))
Likely pathogenic
(Jan 4, 2017)
unknownclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV000837764Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Pathogenic
(Jul 2, 2018)
unknownclinical testing

Citation Link,

SCV004015249KCCC/NGS Laboratory, Kuwait Cancer Control Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jul 7, 2023)
unknownclinical testing

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

SCV004198938Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 9, 2023)
unknownclinical testing

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

SCV004841402All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 13, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown5not providednot provided108544not providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

MUTYH-associated polyposis--from defect in base excision repair to clinical genetic testing.

Cheadle JP, Sampson JR.

DNA Repair (Amst). 2007 Mar 1;6(3):274-9. Epub 2006 Dec 11. Review.

PubMed [citation]
PMID:
17161978

The thorough screening of the MUTYH gene in a large French cohort of sporadic colorectal cancers.

Küry S, Buecher B, Robiou-du-Pont S, Scoul C, Colman H, Lelièvre B, Olschwang S, Le Houérou C, Le Neel T, Faroux R, Ollivry J, Lafraise B, Chupin LD, Bézieau S.

Genet Test. 2007 Winter;11(4):373-9.

PubMed [citation]
PMID:
17931073
See all PubMed Citations (13)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000357900.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

The c.721C>T (p.Arg241Trp) variant, also referred to as c.679C>T (p.Arg227Trp), has been reported in five studies in which it is found in a total of six MYH-associated polyposis patients, including two siblings in a homozygous state and four patients in a compound heterozygous state with one of the common pathogenic MUTYH missense variants (Isidro et al. 2004; Fleischmann et al. 2004; Bai et al. 2005; Torrezan et al. 2013; Guarinos et al. 2014). The variant was absent from 354 controls (Fleischmann et al. 2004) but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg241Trp variant has a severe defect in adenine (A) /7,8-dihydro-8-oxo-guanine binding and therefore in the ability to catalyze adenine excision from A/GO mismatches, one of the main functions of the protein. The p.Arg241Trp variant was also shown to have no detectable glycosylase activity and failed to complement mut Y-deficiency in E. coli. The variant does not affect binding to the hMSH2/hMSH6 complex (Bai et al. 2005; Komine et al. 2015). Based on the collective evidence, the p.Arg241Trp variant is classified as likely pathogenic for MYH-associated polyposis.

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

From Invitae, SCV000545770.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 241 of the MUTYH protein (p.Arg241Trp). This variant is present in population databases (rs34126013, gnomAD 0.03%). This missense change has been observed in individuals with colorectal cancer and/or polyposis (PMID: 14991577, 23561487, 24470512, 27194394). This variant is also known as c.679C>T (p.Arg227Trp). ClinVar contains an entry for this variant (Variation ID: 185274). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15673720, 25820570). This variant disrupts the p.Arg241 amino acid residue in MUTYH. Other variant(s) that disrupt this residue have been observed in individuals with MUTYH-related conditions (PMID: 19732775; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

From Counsyl, SCV000678194.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV000837764.2

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

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004015249.1

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

Description

MUTYH p.Arg241Trp: This sequence change replaces arginine with tryptophan at codon 241 of the MUTYH protein (p.Arg241Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs34126013, ExAC 0.04%). This variant has been reported as heterozygous with another pathogenic variant in MUTYH in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 24470512, 14991577, 27194394), and as homozygous in two siblings from a family affected with polyposis (PMID: 23561487). ClinVar contains an entry for this variant (Variation ID: 185274). In addition, in-silico prediction for this alteration shows pathogenic computational verdict based on 12 pathogenic predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT vs 1 benign prediction from PrimateAI. Experimental studies suggest that this missense change disrupts MUTYH protein function in vitro and in a bacteria-based functional assay (PMID: 15673720, 25820570). Therefore, this variant has been classified as Likely Pathogenic.

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

From Baylor Genetics, SCV004198938.1

#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, SCV004841402.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (9)

Description

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.679C>T (p.Arg227Trp) based on an alternative transcript (NM_001048171). Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant disrupts MUTYH protein function (PMID: 15673720, 25820570). This variant has been reported as compound heterozygous with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 14991577, 15366000, 24470512, 27194394, 28533537, Color internal data), and as homozygous in two siblings affected with attenuated polyposis (parents were consanguineous) (PMID: 23561487). This variant has been identified in 18/281720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided5not providednot providednot provided

Last Updated: May 12, 2024