NM_000051.4(ATM):c.9061G>T (p.Glu3021Ter) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001221353.14

Allele description [Variation Report for NM_000051.4(ATM):c.9061G>T (p.Glu3021Ter)]

NM_000051.4(ATM):c.9061G>T (p.Glu3021Ter)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.9061G>T (p.Glu3021Ter)

HGVS:

NC_000011.10:g.108365398G>T
NG_009830.1:g.147567G>T
NG_054724.1:g.109435C>A
NM_000051.4:c.9061G>TMANE SELECT
NM_001330368.2:c.640+20522C>A
NM_001351110.2:c.694+20522C>A
NM_001351834.2:c.9061G>T
NP_000042.3:p.Glu3021Ter
NP_000042.3:p.Glu3021Ter
NP_001338763.1:p.Glu3021Ter
LRG_135t1:c.9061G>T
LRG_135:g.147567G>T
LRG_135p1:p.Glu3021Ter
NC_000011.9:g.108236125G>T
NM_000051.3:c.9061G>T

Protein change:

E3021*

Links:

dbSNP: rs2091244384

NCBI 1000 Genomes Browser:

rs2091244384

Molecular consequence:

NM_001330368.2:c.640+20522C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.694+20522C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.9061G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.9061G>T - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001393393	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10817650, 16603769, 19781682, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001393393

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.

Li A, Swift M.

Am J Med Genet. 2000 May 29;92(3):170-7.

PubMed [citation]

PMID:: 10817650

The FATC domains of PIKK proteins are functionally equivalent and participate in the Tip60-dependent activation of DNA-PKcs and ATM.

Jiang X, Sun Y, Chen S, Roy K, Price BD.

J Biol Chem. 2006 Jun 9;281(23):15741-6. Epub 2006 Apr 9.

PubMed [citation]

PMID:: 16603769

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001393393.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Glu3021*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the ATM protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 949801). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ATM protein in which other variant(s) (p.Phe3049Profs*13) have been determined to be pathogenic (PMID: 10817650, 16603769, 19781682). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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