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

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 13, 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:: RCV000369240.24

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:

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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Homo sapiens zinc finger protein 385A (ZNF385A), transcript variant 4, mRNA
Homo sapiens zinc finger protein 385A (ZNF385A), transcript variant 4, mRNA
gi|1677531528|ref|NM_001290001.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000357900	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15366000, 15673720, 25820570, 14991577, 17161978, 17931073, 24470512, 23561487 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000545770	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14991577, 23561487, 24470512, 27194394, 15673720, 25820570, 19732775, 28492532
SCV000678194	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 4, 2017)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25820570, 24470512, 15366000, 27194394, 23561487, 14991577, 15673720 Citation Link,
SCV000837764	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV004015249	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004198938	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841402	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 14991577, 15366000, 15673720, 23561487, 24470512, 25820570, 27194394, 28533537, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545770.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000678194.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000837764.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004198938.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004841402.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Oct 20, 2024

Relating variation to medicine