NM_000051.4(ATM):c.9169T>G (p.Ter3057Gly) AND Ataxia-telangiectasia syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 22, 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:: RCV001037761.15

Allele description [Variation Report for NM_000051.4(ATM):c.9169T>G (p.Ter3057Gly)]

NM_000051.4(ATM):c.9169T>G (p.Ter3057Gly)

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.9169T>G (p.Ter3057Gly)

Other names:

*3057G

HGVS:

NC_000011.10:g.108365506T>G
NG_009830.1:g.147675T>G
NG_054724.1:g.109327A>C
NM_000051.4:c.9169T>GMANE SELECT
NM_001330368.2:c.640+20414A>C
NM_001351110.2:c.694+20414A>C
NM_001351834.2:c.9169T>G
NP_000042.3:p.Ter3057Gly
NP_000042.3:p.Ter3057Gly
NP_001338763.1:p.Ter3057Gly
LRG_135t1:c.9169T>G
LRG_135:g.147675T>G
LRG_135p1:p.Ter3057Gly
NC_000011.9:g.108236233T>G
NM_000051.3:c.9169T>G

Links:

dbSNP: rs2091262473

NCBI 1000 Genomes Browser:

rs2091262473

Molecular consequence:

NM_001330368.2:c.640+20414A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.694+20414A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.9169T>G - stop lost - [Sequence Ontology: SO:0001578]
NM_001351834.2:c.9169T>G - stop lost - [Sequence Ontology: SO:0001578]

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

Recent activity

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Salmonella enterica strain A21/157-8, whole genome shotgun sequencing project
Salmonella enterica strain A21/157-8, whole genome shotgun sequencing project
gi|2444597830|gb|ABKQPT000000000.1| T010000000

Nucleotide
BTB (POZ) domain containing 7 [Homo sapiens]
BTB (POZ) domain containing 7 [Homo sapiens]
gi|146327817|gb|AAI41851.1|

Protein
CASP8AP2 caspase 8 associated protein 2 [Homo sapiens]
CASP8AP2 caspase 8 associated protein 2 [Homo sapiens]
Gene ID:9994

Gene
Gene Links for Nucleotide (Select 2462496943) (1)
Gene
Nucleotide INSDC for Assembly (Select 17388468) (0)
Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001201190	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (May 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8845835, 17910737, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001201190

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (3)
[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

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

Large genomic mutations within the ATM gene detected by MLPA, including a duplication of 41 kb from exon 4 to 20.

Cavalieri S, Funaro A, Pappi P, Migone N, Gatti RA, Brusco A.

Ann Hum Genet. 2008 Jan;72(Pt 1):10-8. Epub 2007 Oct 3.

PubMed [citation]

PMID:: 17910737

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001201190.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant results in an extension of the ATM protein. Other variant(s) that result in a similarly extended protein product (p.*3057Serext*29) have been observed in individuals with ATM-related disease (PMID: 8845835). This suggests that these extensions may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 836593). This protein extension has been observed in individual(s) with ataxia telangiectasia (PMID: 17910737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the ATM mRNA. It is expected to extend the length of the ATM protein by 29 additional amino acid residues.

#	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 12, 2024

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