NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 11, 2023
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:: RCV000671308.21

Allele description [Variation Report for NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter)]

NM_000051.4(ATM):c.5692C>T (p.Arg1898Ter)

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.5692C>T (p.Arg1898Ter)

HGVS:

NC_000011.10:g.108307914C>T
NG_009830.1:g.90083C>T
NG_054724.1:g.166919G>A
NM_000051.4:c.5692C>TMANE SELECT
NM_001351834.2:c.5692C>T
NP_000042.3:p.Arg1898Ter
NP_000042.3:p.Arg1898Ter
NP_001338763.1:p.Arg1898Ter
LRG_135t1:c.5692C>T
LRG_135:g.90083C>T
LRG_135p1:p.Arg1898Ter
NC_000011.9:g.108178641C>T
NM_000051.3:c.5692C>T

Protein change:

R1898*

Links:

dbSNP: rs775036118

NCBI 1000 Genomes Browser:

rs775036118

Molecular consequence:

NM_000051.4:c.5692C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.5692C>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
SCV000796269	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Dec 8, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17124347, 23322442 Citation Link,
SCV000956854	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23807571, 25614872, 17124347, 23322442, 23454770, 25077176, 25374739, 28724667, 28492532
SCV001158445	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 22, 2019)	germline	clinical testing	Citation Link,
SCV001337784	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 17, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17124347, 21665257, 30287823, 30982232, 25077176, 25374739 Citation Link,
SCV001452327	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing

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
not provided	unknown	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 (12)

Details of each submission

From Counsyl, SCV000796269.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000956854.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Arg1898*) 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). This variant is present in population databases (rs775036118, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 17124347, 23322442, 23454770, 25077176, 25374739, 28724667). ClinVar contains an entry for this variant (Variation ID: 482526). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001158445.1

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

#	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, SCV001337784.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: ATM c.5692C>T (p.Arg1898X) 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 allele was found at a frequency of 8e-06 in 251006 control chromosomes (gnomAD). c.5692C>T has been reported in the literature in multiple individuals affected with Breast Cancer or Ataxia-Telangiectasia (eg. Magliozzi_2006, Micol_2011, Nespoli_2013, Nakamura_2014, Momozawa_2018, Wang_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was 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

From Natera, Inc., SCV001452327.1

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

#	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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