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NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys) AND Carcinoma of colon

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jul 24, 2014
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000144640.4

Allele description [Variation Report for NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)]

NM_001048174.2(MUTYH):c.1192C>T (p.Arg398Cys)

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.1192C>T (p.Arg398Cys)
Other names:
p.R426C:CGT>TGT
HGVS:
  • NC_000001.11:g.45331467G>A
  • NG_008189.1:g.14004C>T
  • NM_001048171.2:c.1192C>T
  • NM_001048172.2:c.1195C>T
  • NM_001048173.2:c.1192C>T
  • NM_001048174.2:c.1192C>TMANE SELECT
  • NM_001128425.2:c.1276C>T
  • NM_001293190.2:c.1237C>T
  • NM_001293191.2:c.1225C>T
  • NM_001293192.2:c.916C>T
  • NM_001293195.2:c.1192C>T
  • NM_001293196.2:c.916C>T
  • NM_001350650.2:c.847C>T
  • NM_001350651.2:c.847C>T
  • NM_012222.3:c.1267C>T
  • NP_001041636.1:p.Arg412Cys
  • NP_001041636.2:p.Arg398Cys
  • NP_001041637.1:p.Arg399Cys
  • NP_001041638.1:p.Arg398Cys
  • NP_001041639.1:p.Arg398Cys
  • NP_001121897.1:p.Arg426Cys
  • NP_001121897.1:p.Arg426Cys
  • NP_001280119.1:p.Arg413Cys
  • NP_001280120.1:p.Arg409Cys
  • NP_001280121.1:p.Arg306Cys
  • NP_001280124.1:p.Arg398Cys
  • NP_001280125.1:p.Arg306Cys
  • NP_001337579.1:p.Arg283Cys
  • NP_001337580.1:p.Arg283Cys
  • NP_036354.1:p.Arg423Cys
  • NP_036354.1:p.Arg423Cys
  • LRG_220t1:c.1276C>T
  • LRG_220:g.14004C>T
  • LRG_220p1:p.Arg426Cys
  • NC_000001.10:g.45797139G>A
  • NM_001048171.1:c.1234C>T
  • NM_001048174.1:c.1192C>T
  • NM_001048174.2:c.1192C>T
  • NM_001128425.1:c.1276C>T
  • NM_012222.2:c.1267C>T
  • NR_146882.2:n.1420C>T
  • NR_146883.2:n.1269C>T
  • p.R426C
Protein change:
R283C
Links:
dbSNP: rs150792276
NCBI 1000 Genomes Browser:
rs150792276
Molecular consequence:
  • NM_001048171.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.1276C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.1237C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.1192C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.916C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.1267C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.1420C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.1269C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Carcinoma of colon (CRC)
Synonyms:
Colonic carcinoma; Colon carcinoma
Identifiers:
MONDO: MONDO:0002032; MedGen: C0699790

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000189967Pathway Genomics
no assertion criteria provided
Uncertain significance
(Jul 24, 2014) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000592715Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided
Uncertain significanceunknownclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W.

Int J Cancer. 2006 Aug 15;119(4):807-14.

PubMed [citation]
PMID:
16557584

Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli.

Aceto G, Curia MC, Veschi S, De Lellis L, Mammarella S, Catalano T, Stuppia L, Palka G, Valanzano R, Tonelli F, Casale V, Stigliano V, Cetta F, Battista P, Mariani-Costantini R, Cama A.

Hum Mutat. 2005 Oct;26(4):394.

PubMed [citation]
PMID:
16134147
See all PubMed Citations (4)

Details of each submission

From Pathway Genomics, SCV000189967.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV000592715.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The MUTYH p.Arg426Cys variant was identified in 15 of 6049 proband chromosomes (frequency: 0.003) from individuals or families with FAP, MAP, early onset colorectal cancer or breast cancer and was present in 1 of 1152 control chromosomes (frequency: 0.001) from healthy individuals (Lopez-Villar 2010, Fleischmann 2004, Aceto 2005, Aretz 2006, Kanter-Smoler 2006, Guarinos 2014, DeRycke 2017, Ricci 2017, Tung 2016). In functional complementation tests using E. coli and monitoring spontaneous mutation rates, the variant was found to be functionally retained (Komine 2015). The variant was also identified in dbSNP (ID: rs150792276) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by GeneDx and nine other submitters) and in UMD (8x as an unvalidated variant). In UMD the variant was identified with co-occurring pathogenic MUTYH variants c.1145G>A, p.Gly382Asp and c.692G>A, p.Arg231His. The variant was also identified by our laboratory in 5 individuals with colon cancer (no co-occurrence with a pathogenic variant). The variant was identified in control databases in 226 of 277022 chromosomes (1 homozygous) at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 24010 chromosomes (freq: 0.0003), Other in 7 of 6454 chromosomes (freq: 0.001), Latino in 8 of 34418 chromosomes (freq: 0.0002), European in 184 of 126606 chromosomes (freq: 0.001), East Asian in 19 of 18866 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg426 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Nov 3, 2024