NM_000051.4(ATM):c.2921+1G>T AND Ataxia-telangiectasia syndrome

Clinical significance:Pathogenic (Last evaluated: Aug 25, 2020)

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:
RCV000233536.9

Allele description [Variation Report for NM_000051.4(ATM):c.2921+1G>T]

NM_000051.4(ATM):c.2921+1G>T

Gene:
ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q22.3
Genomic location:
Preferred name:
NM_000051.4(ATM):c.2921+1G>T
HGVS:
  • NC_000011.10:g.108271147G>T
  • NG_009830.1:g.53316G>T
  • NM_000051.4:c.2921+1G>TMANE SELECT
  • NM_001351834.2:c.2921+1G>T
  • LRG_135t1:c.2921+1G>T
  • LRG_135:g.53316G>T
  • NC_000011.9:g.108141874G>T
  • NM_000051.3:c.2921+1G>T
Links:
dbSNP: rs587781558
NCBI 1000 Genomes Browser:
rs587781558
Molecular consequence:
  • NM_000051.4:c.2921+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001351834.2:c.2921+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Ataxia-telangiectasia syndrome (AT)
Synonyms:
Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000282914Invitaecriteria provided, single submitter
Pathogenic
(Aug 25, 2020)
germlineclinical testing

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

SCV000746373Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Pathogenic
(Dec 3, 2017)
inheritedclinical testing

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

Summary from all submissions

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

Citations

PubMed

Inherited DNA-Repair Defects in Colorectal Cancer.

AlDubayan SH, Giannakis M, Moore ND, Han GC, Reardon B, Hamada T, Mu XJ, Nishihara R, Qian Z, Liu L, Yurgelun MB, Syngal S, Garraway LA, Ogino S, Fuchs CS, Van Allen EM.

Am J Hum Genet. 2018 Mar 1;102(3):401-414. doi: 10.1016/j.ajhg.2018.01.018. Epub 2018 Feb 22.

PubMed [citation]
PMID:
29478780
PMCID:
PMC5985280

Predominance of null mutations in ataxia-telangiectasia.

Gilad S, Khosravi R, Shkedy D, Uziel T, Ziv Y, Savitsky K, Rotman G, Smith S, Chessa L, Jorgensen TJ, Harnik R, Frydman M, Sanal O, Portnoi S, Goldwicz Z, Jaspers NG, Gatti RA, Lenoir G, Lavin MF, Tatsumi K, Wegner RD, Shiloh Y, et al.

Hum Mol Genet. 1996 Apr;5(4):433-9.

PubMed [citation]
PMID:
8845835
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000282914.8

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

Description

This sequence change affects a donor splice site in intron 19 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual with colorectal cancer (PMID: 29478780). ClinVar contains an entry for this variant (Variation ID: 142057). A different variant affecting this nucleotide (c.2921+1G>A), also referred to in the literature as 2983del83 and IVS21+1G>A), has been reported in multiple individuals affected with ataxia-telangiectasia (PMID: 8845835, 11298136). Functional studies have demonstrated that this change causes skipping of exon 19 (also referred to as exon 21), leading to a frameshift and a premature stop codon (p.Tyr947Glnfs*9). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

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

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000746373.1

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

Last Updated: Nov 27, 2021

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