NM_001048174.2(MUTYH):c.493-5A>G AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Oct 19, 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_001048174.2(MUTYH):c.493-5A>G]


MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000001.11:g.45332692T>C
  • NG_008189.1:g.12779A>G
  • NM_001048171.1:c.535-5A>G
  • NM_001048171.2:c.493-5A>G
  • NM_001048172.1:c.496-5A>G
  • NM_001048173.1:c.493-5A>G
  • NM_001048174.2:c.493-5A>GMANE SELECT
  • NM_001128425.1:c.577-5A>G
  • NM_001128425.2:c.577-5A>G
  • NM_001293190.1:c.538-5A>G
  • NM_001293191.1:c.526-5A>G
  • NM_001293192.1:c.217-5A>G
  • NM_001293195.1:c.493-5A>G
  • NM_001293196.1:c.217-5A>G
  • NM_001350650.1:c.148-5A>G
  • NM_001350651.1:c.148-5A>G
  • NM_012222.2:c.568-5A>G
  • LRG_220t1:c.577-5A>G
  • LRG_220:g.12779A>G
  • NC_000001.10:g.45798364T>C
dbSNP: rs758377868
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001048171.1:c.535-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048171.2:c.493-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048172.1:c.496-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048173.1:c.493-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048174.2:c.493-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001128425.1:c.577-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001128425.2:c.577-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293190.1:c.538-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293191.1:c.526-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293192.1:c.217-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293195.1:c.493-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293196.1:c.217-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001350650.1:c.148-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001350651.1:c.148-5A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_012222.2:c.568-5A>G - intron variant - [Sequence Ontology: SO:0001627]


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)
SCV000212816Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 24, 2019)
germlineclinical testing

Citation Link,

SCV000685648Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Oct 19, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000212816.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.577-5A>G intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 8 in the MUTYH gene. This variant has been identified in conjunction with pathogenic MUTYH mutations in probands with adenomatous polyposis (Ambry internal data). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site. However, the Human Splicing Finder (HSF) software predicts the creation of a new alternate splice acceptor site, and the MaxEnt splice site prediction tool predicts a weakening of the native splice acceptor site efficiency (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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, SCV000685648.3

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


This variant causes an A to G nucleotide substitution at the -5 position of intron 7 of the MUTYH gene. A functional RNA study has shown that this variant causes aberrant splicing and results in a partial intron 7 retention (r.576_577ins577-4_577-1), which is predicted to cause a frameshift and premature protein truncation (PMID: 32133419). It has been shown that the mutant transcript constitutes about 16% relative transcript level in cells from a heterozygous carrier (PMID: 32133419). This variant has been observed together with a known pathogenic mutation, p.Gly396Asp, in the same gene in two individuals affected with severe polyposis (PMID: 32133419). This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: Aug 17, 2021

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