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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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000213238Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Aug 25, 2022) 		germlineclinical testing

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

Citation Link,

SCV000690558Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 10, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

From Color Diagnostics, LLC DBA Color Health, SCV000690558.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Sep 29, 2024