NM_000051.4(ATM):c.4104_4105del (p.Ser1369fs) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 29, 2022
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:: RCV000807392.6

Allele description [Variation Report for NM_000051.4(ATM):c.4104_4105del (p.Ser1369fs)]

NM_000051.4(ATM):c.4104_4105del (p.Ser1369fs)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.4104_4105del (p.Ser1369fs)

HGVS:

NC_000011.10:g.108287710_108287711del
NG_009830.1:g.69879_69880del
NM_000051.4:c.4104_4105delMANE SELECT
NM_001351834.2:c.4104_4105del
NP_000042.3:p.Ser1369fs
NP_001338763.1:p.Ser1369fs
LRG_135:g.69879_69880del
NC_000011.9:g.108158435_108158436del
NC_000011.9:g.108158437_108158438del
NM_000051.3:c.4104_4105delTT
NM_000051.4:c.4104_4105del

Protein change:

S1369fs

Links:

dbSNP: rs879254189

NCBI 1000 Genomes Browser:

rs879254189

Molecular consequence:

NM_000051.4:c.4104_4105del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.4104_4105del - frameshift variant - [Sequence Ontology: SO:0001589]

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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V(D)J recombination-activating protein 2 isoform X1 [Rattus norvegicus]
V(D)J recombination-activating protein 2 isoform X1 [Rattus norvegicus]
gi|2678927934|ref|XP_063139376.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000947440	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23807571, 25614872, 28492532
SCV002511534	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 25, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000947440

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 29, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002511534

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 25, 2022)

germline

clinical testing

Citation Link

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

Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.

Huang Y, Yang L, Wang J, Yang F, Xiao Y, Xia R, Yuan X, Yan M.

Neuromolecular Med. 2013 Sep;15(3):536-40. doi: 10.1007/s12017-013-8240-3. Epub 2013 Jun 27. Erratum in: Neuromolecular Med. 2014 Mar;16(1):216.

PubMed [citation]

PMID:: 23807571
PMCID:: PMC3732755

Ten new ATM alterations in Polish patients with ataxia-telangiectasia.

Podralska MJ, Stembalska A, Ślęzak R, Lewandowicz-Uszyńska A, Pietrucha B, Kołtan S, Wigowska-Sowińska J, Pilch J, Mosor M, Ziółkowska-Suchanek I, Dzikiewicz-Krawczyk A, Słomski R.

Mol Genet Genomic Med. 2014 Nov;2(6):504-11. doi: 10.1002/mgg3.98. Epub 2014 Jul 30.

PubMed [citation]

PMID:: 25614872
PMCID:: PMC4303220

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000947440.6

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

Description

This sequence change creates a premature translational stop signal (p.Ser1369Argfs*8) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 246275). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511534.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: ATM c.4104_4105delTT (p.Ser1369ArgfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248440 control chromosomes. To our knowledge, no occurrence of c.4104_4105delTT in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely 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: Sep 29, 2024

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