NM_001048174.2(MUTYH):c.637C>T (p.Arg213Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 8, 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:: RCV000164664.13

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215329	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 14, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14991577, 15366000, 15673720, 17931073, 23561487, 30564557, 32338768, 33313162 Citation Link,
SCV000685663	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15366000, 15673720, 19394335, 23561487, 24470512, 25820570, 27194394, 28533537, 34704405, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215329

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 14, 2021)

germline

clinical testing

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

Citation Link,

SCV000685663

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 8, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

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 (15)

Details of each submission

From Ambry Genetics, SCV000215329.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R241W pathogenic mutation (also known as c.721C>T), located in coding exon 9 of the MUTYH gene, results from a C to T substitution at nucleotide position 721. The arginine at codon 241 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in conjunction with the common MUTYH founder mutations p.G396D (p.G382D) and p.Y179C (p.Y165C), other pathogenic/likely pathogenic MUTYH variants, and as homozygous in multiple patients with classic polyposis, attenuated polyposis, and/or colorectal cancer (Isidro G et al. Hum Mutat. 2004 Oct;24(4):353-4; Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Torrezan GT et al. Orphanet J Rare Dis. 2013 ;8:54; Guarinos C et al. Clin Cancer Res. 2014 Mar 1;20(5):1158-68; Win AK et al. Int J Cancer. 2016 Oct 1;139(7):1557-63; Khan N et al. Sci Rep. 2017 May 22;7(1):2214; Ambry internal data). Furthermore, the aforementioned co-occurrences are likely to be in trans due to multiple observances with different pathogenic or likely pathogenic MUTYH variants. In functional assays measuring glycosylase activity and DNA-binding activity, this variant demonstrated impaired protein function similar to the p.Y179C (p.Y165C) MUTYH founder mutation (Bai H et al. Nucleic Acids Res. 2005 Jan 26;33(2):597-604; Komine K et al. Hum Mutat. 2015 Jul;36(7):704-11). This alteration has also been identified in individuals diagnosed with male breast cancer, breast cancer and prostate cancer (Rizzolo P et al. Front Oncol, 2018 Dec;8:583; Lang GT et al. Ann Transl Med, 2020 Nov;8:1417; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). Of note, this alteration is also designated as p.R227W in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000685663.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces arginine with tryptophan at codon 241 of the MUTYH protein. This variant is also known as c.637C>T (p.Arg213Trp) based on an alternative transcript (NM_001048174.2). 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). Functional studies have shown that this variant was deficient in A/8-oxoG binding and glycosylase activities , and failed to complement mutY-deficiency in Escherichia coli (PMID: 15673720, 25820570). This variant has been reported as biallelic with another pathogenic variant in multiple individuals affected with polyposis and/or colorectal cancer (PMID: 15366000, 19394335, 23561487, 24470512, 27194394, 28533537, 34704405). 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 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

Last Updated: Oct 20, 2024

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