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NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (3 submissions)
Last evaluated:
Oct 27, 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:
RCV000131615.21

Allele description [Variation Report for NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe)]

NM_001048174.2(MUTYH):c.652G>T (p.Val218Phe)

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.652G>T (p.Val218Phe)
Other names:
p.V246F:GTC>TTC
HGVS:
  • NC_000001.11:g.45332443C>A
  • NG_008189.1:g.13028G>T
  • NM_001048171.2:c.652G>T
  • NM_001048172.2:c.655G>T
  • NM_001048173.2:c.652G>T
  • NM_001048174.2:c.652G>TMANE SELECT
  • NM_001128425.2:c.736G>T
  • NM_001293190.2:c.697G>T
  • NM_001293191.2:c.685G>T
  • NM_001293192.2:c.376G>T
  • NM_001293195.2:c.652G>T
  • NM_001293196.2:c.376G>T
  • NM_001350650.2:c.307G>T
  • NM_001350651.2:c.307G>T
  • NM_012222.3:c.727G>T
  • NP_001041636.1:p.Val232Phe
  • NP_001041636.2:p.Val218Phe
  • NP_001041637.1:p.Val219Phe
  • NP_001041638.1:p.Val218Phe
  • NP_001041639.1:p.Val218Phe
  • NP_001121897.1:p.Val246Phe
  • NP_001121897.1:p.Val246Phe
  • NP_001280119.1:p.Val233Phe
  • NP_001280120.1:p.Val229Phe
  • NP_001280121.1:p.Val126Phe
  • NP_001280124.1:p.Val218Phe
  • NP_001280125.1:p.Val126Phe
  • NP_001337579.1:p.Val103Phe
  • NP_001337580.1:p.Val103Phe
  • NP_036354.1:p.Val243Phe
  • LRG_220t1:c.736G>T
  • LRG_220:g.13028G>T
  • LRG_220p1:p.Val246Phe
  • NC_000001.10:g.45798115C>A
  • NM_001048171.1:c.694G>T
  • NM_001128425.1:c.736G>T
  • NM_001128425.2:c.736G>T
  • NR_146882.2:n.880G>T
  • NR_146883.2:n.729G>T
  • p.V246F
Protein change:
V103F
Links:
dbSNP: rs587780749
NCBI 1000 Genomes Browser:
rs587780749
Molecular consequence:
  • NM_001048171.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.2:c.655G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.2:c.736G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.2:c.697G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.2:c.685G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.2:c.376G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.2:c.652G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.2:c.376G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.2:c.307G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.2:c.307G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.3:c.727G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.2:n.880G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.729G>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
SCV000186631Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 27, 2023) 		germlineclinical testing

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

Citation Link,

SCV000910970Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Oct 19, 2023) 		germlineclinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV002532326Sema4, Sema4
criteria provided, single submitter

(Sema4 Curation Guidelines)		Likely pathogenic
(Feb 12, 2022) 		germlinecuration

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6.

Gu Y, Parker A, Wilson TM, Bai H, Chang DY, Lu AL.

J Biol Chem. 2002 Mar 29;277(13):11135-42. Epub 2002 Jan 18.

PubMed [citation]
PMID:
11801590

Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC.

PLoS One. 2017;12(2):e0170843. doi: 10.1371/journal.pone.0170843.

PubMed [citation]
PMID:
28152038
PMCID:
PMC5289469
See all PubMed Citations (15)

Details of each submission

From Ambry Genetics, SCV000186631.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (9)

Description

The p.V246F variant (also known as c.736G>T), located in coding exon 9 of the MUTYH gene, results from a G to T substitution at nucleotide position 736. The valine at codon 246 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with adenomatous polyposis who also carried another MUTYH mutation, including one individual with both polyposis and colorectal cancer (Sieber OM et al. N. Engl. J. Med. 2003 Feb;348(9):791-9; Filipe B et al. Clin. Genet. 2009 Sep:76(3):242–55; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57; López-Villar I et al. BMC Cancer. 2010 Aug;10:408). Functional analyses of the mutated protein revealed reduced glycosylase and DNA binding activities compared to the wild type enzyme (Bai H et al. Nucleic Acids Res. 2005 Jan;33(2):597-604). Of note, this alteration is also designated as p.V232F in the published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

From Color Diagnostics, LLC DBA Color Health, SCV000910970.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (13)

Description

This missense variant replaces valine with phenylalanine at codon 246 of the MUTYH protein. This variant is also known as c.694G>T (p.Val232Phe) based on an alternative transcript (NM_001048171). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported this variant protein exhibited partially defective glycosylase and DNA binding activity (PMID: 15673720) but showed conflicting results in E. coli complementation assays, from defective to wild-type activity (PMID: 15673720, 25820570). This variant has been reported in individuals affected with multiple adenomas or polyposis (PMID: 12606733, 19793053, 20687945). At least one of these individuals carried a second pathogenic MUTYH variant in the compound heterozygous state (PMID: 12606733) while another individual carried a MUTYH variant of uncertain significance in trans (PMID: 20687945). This variant has also been reported in individuals affected with colorectal cancer, including one individual who carried this variant in the homozygous state (PMID: 19531215; ClinVar SCV000186631.8). In addition, this variant has been observed in individuals affected with gastrointestinal/neuroendocrine tumors (PMID: 26556299), bilateral breast cancer (PMID: 24733792), unilateral breast cancer (PMID: 33471991, 35264596), and head neck squamous cell carcinoma (PMID: 34598035). This variant has been identified in 14/250286 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

From Sema4, Sema4, SCV002532326.1

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

Last Updated: May 7, 2024