NM_001128425.1(MUTYH):c.847A>G (p.Met283Val) AND not provided

Clinical significance:Pathogenic (Last evaluated: Sep 8, 2015)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000479475.1

Allele description [Variation Report for NM_001128425.1(MUTYH):c.847A>G (p.Met283Val)]

NM_001128425.1(MUTYH):c.847A>G (p.Met283Val)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001128425.1(MUTYH):c.847A>G (p.Met283Val)
HGVS:
  • NC_000001.11:g.45332252T>C
  • NG_008189.1:g.13219A>G
  • NM_001048171.1:c.805A>G
  • NM_001048172.1:c.766A>G
  • NM_001048173.1:c.763A>G
  • NM_001048174.1:c.763A>G
  • NM_001128425.1:c.847A>G
  • NM_001293190.1:c.808A>G
  • NM_001293191.1:c.796A>G
  • NM_001293192.1:c.487A>G
  • NM_001293195.1:c.763A>G
  • NM_001293196.1:c.487A>G
  • NM_001350650.1:c.418A>G
  • NM_001350651.1:c.418A>G
  • NM_012222.2:c.838A>G
  • NP_001041636.1:p.Met269Val
  • NP_001041637.1:p.Met256Val
  • NP_001041638.1:p.Met255Val
  • NP_001041639.1:p.Met255Val
  • NP_001121897.1:p.Met283Val
  • NP_001280119.1:p.Met270Val
  • NP_001280120.1:p.Met266Val
  • NP_001280121.1:p.Met163Val
  • NP_001280124.1:p.Met255Val
  • NP_001280125.1:p.Met163Val
  • NP_001337579.1:p.Met140Val
  • NP_001337580.1:p.Met140Val
  • NP_036354.1:p.Met280Val
  • LRG_220t1:c.847A>G
  • LRG_220:g.13219A>G
  • LRG_220p1:p.Met283Val
  • NC_000001.10:g.45797924T>C
  • NR_146882.1:n.1021A>G
  • NR_146883.1:n.835A>G
Protein change:
M140V
Links:
dbSNP: rs876659676
NCBI 1000 Genomes Browser:
rs876659676
Molecular consequence:
  • NM_001048171.1:c.805A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048172.1:c.766A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048173.1:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001048174.1:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001128425.1:c.847A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293190.1:c.808A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293191.1:c.796A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293192.1:c.487A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293195.1:c.763A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293196.1:c.487A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350650.1:c.418A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001350651.1:c.418A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_012222.2:c.838A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_146882.1:n.1021A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.1:n.835A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000567803GeneDxcriteria provided, single submitter
Pathogenic
(Sep 8, 2015)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000567803.4

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

Description

This pathogenic variant is denoted MUTYH c.847A>G at the cDNA level, p.Met283Val (M283V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant, also published as MUTYH c.805A>G and p.Met269Val as well as c.763A>G and p.Met255Val, has been observed in a compound heterozygous state in three individuals, two of whom were siblings; one was reported to have a history of cecal cancer and the other two had multiple adenomatous polyps (Lejeune 2006, van Puijenbroek 2008). Additionally, MUTYH Met283Val has been shown to severely reduce gycosylase activity in vitro and the ability of MUTYH to repair 8-hydroxyguanine induced DNA damage in human cells compared to wild type controls (Goto 2010, Shinmura 2012). MUTYH Met283Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MUTYH Met283Val occurs at a position that is conserved across species and is located in the FeS cluster (Ruggieri 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.Although this variant is considered pathogenic, a second mutation, as would be required for expression of the recessive condition MAP, was not detected in this individual. The possibility that this patient harbors a second disease-causing MUTYH mutation that is undetectable by this test cannot be excluded. While a single variant in the MUTYH gene has been reported in association with a slightly increased risk for colon cancer, endometrial cancer, and breast cancer, particularly among those with a family history of colorectal cancer (Jenkins 2006, Win 2011, Rennert 2012), there are conflicting data regarding these associations (Santonocito 2011, Out 2012). MUTYH-associated polyposis (MAP) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the MUTYH gene which results in an increased risk for the development of colon cancer and colon polyps. If a MUTYH mutation carrier'spartner is also heterozygous for a MUTYH mutation, the risk to have a child with MAP is 25% with each pregnancy. One study from the UK estimated the overall carrier frequency for any MUTYH mutation to be about 2% (Aretz 2010).

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

Last Updated: Jun 25, 2021

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