NM_001128425.1(MUTYH):c.847A>G (p.Met283Val) AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jan 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

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

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

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_001128425.1(MUTYH):c.847A>G (p.Met283Val)
  • 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:
dbSNP: rs876659676
NCBI 1000 Genomes Browser:
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]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000276384Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Jan 22, 2018)
germlineclinical testing

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

Citation Link,

SCV000911616Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Jan 3, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]


This missense variant replaces methionine with valine at codon 283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have reported the variant protein to be defective in the suppression of oxidative mutagenesis when expressed in human cell lines (PMID: 23322991) and in adenine DNA glycosylase assay in vitro (PMID: 20848659). This variant has been reported with a pathogenic MUTYH co-variant in two families affected with cancer of the cecum and colorectal polyposis (PMID: 18172263, 16941501). This variant has been identified in 1/250754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis.

Lejeune S, Guillemot F, Triboulet JP, Cattan S, Mouton C; PAFNORD Group., Porchet N, Manouvrier S, Buisine MP.

Hum Mutat. 2006 Oct;27(10):1064.

PubMed [citation]

Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer.

Goto M, Shinmura K, Nakabeppu Y, Tao H, Yamada H, Tsuneyoshi T, Sugimura H.

Hum Mutat. 2010 Nov;31(11):E1861-74. doi: 10.1002/humu.21363.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000276384.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)


The p.M283V variant (also known as c.847A>G), located in coding exon 10 of the MUTYH gene, results from an A to G substitution at nucleotide position 847. The methionine at codon 283 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in conjunction with a MUTYH pathogenic mutation in patients with multiple adenomas and/or colorectal cancer (Lejeune S et al, Hum. Mutat. 2006 Oct; 27(10):1064; van Puijenbroek M et al. Clin Cancer Res. 2008 Jan 1;14(1):139-42). In addition, functional studies have shown this alteration causes severe impairment in DNA glycosylase activity compared to the wild-type protein (Goto M et al. Hum. Mutat. 2010 Nov; 31(11):E1861-74); as well as suppression of oxidative mutagenesis, thought to severely impair function in human cells (Shinmura K et al. World J. Gastroenterol. 2012 Dec; 18(47):6935-42). Of note, this alteration is also designated as p.M269V (c.805A>G) in published literature. 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 majority of available evidence to date, this variant is likely to be pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000911616.2

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

Last Updated: Jun 25, 2021

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