NM_001048174.2(MUTYH):c.241C>T (p.Arg81Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 10, 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:: RCV000162761.15

Allele description [Variation Report for NM_001048174.2(MUTYH):c.241C>T (p.Arg81Trp)]

NM_001048174.2(MUTYH):c.241C>T (p.Arg81Trp)

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.241C>T (p.Arg81Trp)

HGVS:

NC_000001.11:g.45333436G>A
NG_008189.1:g.12035C>T
NM_001048171.2:c.241C>T
NM_001048172.2:c.244C>T
NM_001048173.2:c.241C>T
NM_001048174.2:c.241C>TMANE SELECT
NM_001128425.2:c.325C>T
NM_001293190.2:c.286C>T
NM_001293191.2:c.274C>T
NM_001293192.2:c.-36C>T
NM_001293195.2:c.241C>T
NM_001293196.2:c.-36C>T
NM_001350650.2:c.-31C>T
NM_001350651.2:c.-31C>T
NM_012222.3:c.316C>T
NP_001041636.1:p.Arg95Trp
NP_001041636.2:p.Arg81Trp
NP_001041637.1:p.Arg82Trp
NP_001041638.1:p.Arg81Trp
NP_001041639.1:p.Arg81Trp
NP_001121897.1:p.Arg109Trp
NP_001121897.1:p.Arg109Trp
NP_001280119.1:p.Arg96Trp
NP_001280120.1:p.Arg92Trp
NP_001280124.1:p.Arg81Trp
NP_036354.1:p.Arg106Trp
LRG_220t1:c.325C>T
LRG_220:g.12035C>T
LRG_220p1:p.Arg109Trp
NC_000001.10:g.45799108G>A
NM_001048171.1:c.283C>T
NM_001128425.1:c.325C>T
NR_146882.2:n.469C>T
NR_146883.2:n.392C>T
p.R109W

Protein change:

R106W

Links:

dbSNP: rs765123255

NCBI 1000 Genomes Browser:

rs765123255

Molecular consequence:

NM_001293192.2:c.-36C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001293196.2:c.-36C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350650.2:c.-31C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001350651.2:c.-31C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001048171.2:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.244C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.325C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.274C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.316C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.469C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.392C>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

Recent activity

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type II restriction endonuclease [Shewanella oneidensis MR-1]
type II restriction endonuclease [Shewanella oneidensis MR-1]
gi|24371902|gnl|REF_tigr|SO_0304|re 715944.1|

Protein
RecName: Full=Tubulin alpha chain-like 3
RecName: Full=Tubulin alpha chain-like 3
gi|342187030|sp|Q3UX10.2|TBAL3_MOUS

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000213238	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 25, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19394335, 19414147, 24799981, 25197429, 25980754, 26600934, 27145315, 29406563, 30604180 Citation Link,
SCV000690558	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 10, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 517270, 19394335, 19527492, 19732775, 24799981, 25980754, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213238

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Aug 25, 2022)

germline

clinical testing

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

Citation Link,

SCV000690558

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 10, 2023)

germline

clinical testing

PubMed (7)
[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

MUTYH-associated polyposis.

Sampson JR, Jones N.

Best Pract Res Clin Gastroenterol. 2009;23(2):209-18. doi: 10.1016/j.bpg.2009.03.006. Review.

PubMed [citation]

PMID:: 19414147

Oxidative damage to nucleic acids and benzo(a)pyrene-7,8-diol-9,10-epoxide-DNA adducts and chromosomal aberration in children with psoriasis repeatedly exposed to crude coal tar ointment and UV radiation.

Borska L, Andrys C, Krejsek J, Palicka V, Chmelarova M, Hamakova K, Kremlacek J, Fiala Z.

Oxid Med Cell Longev. 2014;2014:302528. doi: 10.1155/2014/302528. Epub 2014 Aug 12.

PubMed [citation]

PMID:: 25197429
PMCID:: PMC4146480

See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000213238.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.R109W variant (also known as c.325C>T), located in coding exon 3 of the MUTYH gene, results from a C to T substitution at nucleotide position 325. The arginine at codon 109 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been identified, in conjunction with a pathogenic MUTYH mutation, in multiple patients with colorectal cancer and/or polyposis (Vogt et al. Gastroenterology. 2009;137:1976–1985; Yurgelun MB et al. Gastroenterology 2015 Sep;149:604-13.e20; Church J et al. Dis. Colon Rectum, 2016 Jun;59:565; Ambry internal data). This alteration was also identified in 1 of 34 patients with colorectal cancer under age 43 from a cohort of 685 Japanese patients and was associated with severely reduced MUTYH protein function (Shinmura K et al. Oxid Med Cell Longev 2014;2014:617351). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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, SCV000690558.5

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

Description

This missense variant replaces arginine with tryptophan at codon 109 of the MUTYH protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant disrupts the DNA glycosylase activity of the MUTYH protein and its ability to suppress mutations (PMID: 24799981). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis and colorectal cancer (PMID: 19394335, 19527492, 19732775; ClinVar SCV000517270.5) and in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has also been observed in a heterozygous individual affected with early-onset colorectal cancer (PMID: 24799981). This variant has been identified in 11/282856 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: Sep 29, 2024

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