NM_001048174.2(MUTYH):c.775del (p.Ala259fs) AND MYH-associated polyposis

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 17, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000499908.5

Allele description [Variation Report for NM_001048174.2(MUTYH):c.775del (p.Ala259fs)]

NM_001048174.2(MUTYH):c.775del (p.Ala259fs)

Gene:
MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
1p34.1
Genomic location:
Preferred name:
NM_001048174.2(MUTYH):c.775del (p.Ala259fs)
HGVS:
  • NC_000001.10:g.45797912del
  • NC_000001.11:g.45332243del
  • NG_008189.1:g.13231del
  • NM_001048171.2:c.775del
  • NM_001048172.2:c.778del
  • NM_001048173.2:c.775del
  • NM_001048174.2:c.775delMANE SELECT
  • NM_001128425.1:c.859del
  • NM_001128425.2:c.859del
  • NM_001293190.2:c.820del
  • NM_001293191.2:c.808del
  • NM_001293192.2:c.499del
  • NM_001293195.2:c.775del
  • NM_001293196.2:c.499del
  • NM_001350650.2:c.430del
  • NM_001350651.2:c.430del
  • NM_012222.3:c.850del
  • NP_001041636.2:p.Ala259fs
  • NP_001041637.1:p.Ala260fs
  • NP_001041638.1:p.Ala259fs
  • NP_001041639.1:p.Ala259fs
  • NP_001121897.1:p.Ala287fs
  • NP_001121897.1:p.Ala287fs
  • NP_001280119.1:p.Ala274fs
  • NP_001280120.1:p.Ala270fs
  • NP_001280121.1:p.Ala167fs
  • NP_001280124.1:p.Ala259fs
  • NP_001280125.1:p.Ala167fs
  • NP_001337579.1:p.Ala144fs
  • NP_001337580.1:p.Ala144fs
  • NP_036354.1:p.Ala284fs
  • LRG_220t1:c.859del
  • LRG_220:g.13231del
  • LRG_220p1:p.Ala287fs
  • NC_000001.10:g.45797912del
  • NC_000001.10:g.45797912delC
  • NC_000001.10:g.45797915del
  • NM_001128425.1:c.859delG
  • NR_146882.2:n.1003del
  • NR_146883.2:n.852del
  • p.Ala287ProfsX32
Protein change:
A144fs
Links:
dbSNP: rs761468459
NCBI 1000 Genomes Browser:
rs761468459
Molecular consequence:
  • NM_001048171.2:c.775del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048172.2:c.778del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048173.2:c.775del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001048174.2:c.775del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001128425.1:c.859del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001128425.2:c.859del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293190.2:c.820del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293191.2:c.808del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293192.2:c.499del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293195.2:c.775del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001293196.2:c.499del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350650.2:c.430del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001350651.2:c.430del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_012222.3:c.850del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_146882.2:n.1003del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_146883.2:n.852del - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
MYH-associated polyposis (FAP2)
Synonyms:
COLORECTAL ADENOMATOUS POLYPOSIS, AUTOSOMAL RECESSIVE; ADENOMAS, MULTIPLE COLORECTAL, AUTOSOMAL RECESSIVE; FAP type 2; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012041; MedGen: C3272841; Orphanet: 220460; OMIM: 608456

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000967776Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Sep 6, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001399526Invitaecriteria provided, single submitter
Pathogenic
(Aug 17, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, Mangold E, Caspari R, Propping P, Friedl W.

Int J Cancer. 2006 Aug 15;119(4):807-14.

PubMed [citation]
PMID:
16557584
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967776.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The p.Ala287ProfsX32 variant in MUTYH has been reported in the heterozygous stat e in one individuals with familial adenomatouspolyposis (Aretz 20016). It has al so been identified in 1/30782 of South Asian chromosomes by gnomAD (http://gnoma d.broadinstitute.org). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 287 and leads to a premature termination codon 32 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, although addition al studies are required to fully establish its clinical significance, the p.Ala2 87ProfsX32 variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Invitae, SCV001399526.2

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

Description

This sequence change creates a premature translational stop signal (p.Ala287Profs*32) in the MUTYH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761468459, ExAC 0.006%). This variant has been observed in an individual affected with polyposis (PMID: 16557584). This variant is also known as c.817delG, p.A273PfsX32 in the literature. ClinVar contains an entry for this variant (Variation ID: 433934). Loss-of-function variants in MUTYH are known to be pathogenic (PMID: 18534194, 20663686). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 25, 2021

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