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NM_001048174.2(MUTYH):c.420+19_420+31del AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Feb 19, 2024
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:
RCV000580373.11

Allele description [Variation Report for NM_001048174.2(MUTYH):c.420+19_420+31del]

NM_001048174.2(MUTYH):c.420+19_420+31del

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048174.2(MUTYH):c.420+19_420+31del
HGVS:
  • NC_000001.10:g.45798561_45798573delTATTTCCCCTACC
  • NC_000001.11:g.45332889_45332901del
  • NG_008189.1:g.12572_12584del
  • NM_001048171.2:c.420+19_420+31del
  • NM_001048172.2:c.423+19_423+31del
  • NM_001048173.2:c.420+19_420+31del
  • NM_001048174.2:c.420+19_420+31delMANE SELECT
  • NM_001128425.2:c.504+19_504+31del
  • NM_001293190.2:c.465+19_465+31del
  • NM_001293191.2:c.453+19_453+31del
  • NM_001293192.2:c.144+19_144+31del
  • NM_001293195.2:c.420+19_420+31del
  • NM_001293196.2:c.144+19_144+31del
  • NM_001350650.2:c.75+19_75+31del
  • NM_001350651.2:c.75+19_75+31del
  • NM_012222.3:c.495+19_495+31del
  • LRG_220t1:c.504+19_504+31del
  • LRG_220:g.12572_12584del
  • NC_000001.10:g.45798559_45798571del
  • NC_000001.10:g.45798561_45798573del
  • NC_000001.10:g.45798561_45798573del
  • NC_000001.10:g.45798561_45798573delTATTTCCCCTACC
  • NM_001048174.2:c.420+19_420+31del
  • NM_001128425.1:c.504+19_504+31del
  • NM_001128425.1:c.504+19_504+31del
  • NM_001128425.1:c.504+19_504+31delTAGGGGAAATAGG
  • NM_001128425.2:c.504+19_504+31del
Links:
dbSNP: rs781222233
NCBI 1000 Genomes Browser:
rs781222233
Molecular consequence:
  • NM_001048171.2:c.420+19_420+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048172.2:c.423+19_423+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048173.2:c.420+19_420+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001048174.2:c.420+19_420+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001128425.2:c.504+19_504+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293190.2:c.465+19_465+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293191.2:c.453+19_453+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293192.2:c.144+19_144+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293195.2:c.420+19_420+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001293196.2:c.144+19_144+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001350650.2:c.75+19_75+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001350651.2:c.75+19_75+31del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_012222.3:c.495+19_495+31del - intron variant - [Sequence Ontology: SO:0001627]

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000685635Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jun 14, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001185342Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(Feb 19, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations.

Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E.

Clin Genet. 2010 Oct;78(4):353-63. doi: 10.1111/j.1399-0004.2010.01478.x.

PubMed [citation]
PMID:
20618354

Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study.

Ricci MT, Miccoli S, Turchetti D, Bondavalli D, Viel A, Quaia M, Giacomini E, Gismondi V, Sanchez-Mete L, Stigliano V, Martayan A, Mazzei F, Bignami M, Bonelli L, Varesco L.

J Hum Genet. 2017 Feb;62(2):309-315. doi: 10.1038/jhg.2016.132. Epub 2016 Nov 10.

PubMed [citation]
PMID:
27829682
See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000685635.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This variant causes a 13 base pair deletion in intron 6 of the MUTYH gene. An RNA study found this variant resulted in the in-frame skipping of exon 6 (PMID: 20628285). This variant has been reported in compound heterozygous and homozygous carriers with polyposis and/or colorectal cancer (PMID: 16890597, 19732775, 20618354, 20628285, 26446593, 27829682). In particular, this variant was observed in the compound heterozygous state with a pathogenic variant, c.1437_1439del, in an individual affected with polyps and colorectal cancer (PMID: 20628285). The proband's mother, who was heterozygous for this variant, as well as the proband's sister, who was heterozygous for c.1437_1439del variant, were unaffected with polyps and colorectal cancer. This variant was also observed in homozygosity in three siblings in a different family (PMID: 20628285). Their heterozygous mother, father, and one sibling were unaffected with polyps and colorectal cancer (PMID: 20628285). This variant has been identified in 2/251048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). 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 Ambry Genetics, SCV001185342.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The c.504+19_504+31del13 intronic pathogenic mutation is located 19 nucleotides after coding exon 6 in the MUTYH gene. This variant results from a deletion of 13 nucleotides at positions c.504+19 to c.504+31. This variant has been reported in the homozygous state as well as in conjunction with MUTYH pathogenic mutations in individuals with adenomatous polyposis and co-segregated with disease in three affected siblings of a family (Di Gregorio C et al. Gastroenterology, 2006 Aug;131:439-44; Jones N et al. Gastroenterology, 2009 Aug;137:489-94, 494.e1; quiz 725-6; Vogt S et al. Gastroenterology, 2009 Dec;137:1976-85.e1-10; Fostira F et al. Dis. Colon Rectum, 2010 Aug;53:1197-201; Papp J et al. Fam. Cancer, 2016 Jan;15:85-97). Analysis by RT-PCR using RNA from a patient homozygous for this variant and a compound heterozygous patient was reported to result in complete in-frame skipping of MUTYH coding exon 6 (Fostira F et al. Dis. Colon Rectum, 2010 Aug;53:1197-201). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on an internal structural analysis, deletion of MUTYH coding exon 6 would be structurally deleterious (Ambry internal data). These nucleotide positions are not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Jan 13, 2025