NM_000051.4(ATM):c.7456C>T (p.Arg2486Ter) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 14, 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:: RCV000462583.26

Allele description [Variation Report for NM_000051.4(ATM):c.7456C>T (p.Arg2486Ter)]

NM_000051.4(ATM):c.7456C>T (p.Arg2486Ter)

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.7456C>T (p.Arg2486Ter)

Other names:

p.R2486*:CGA>TGA; p.Arg2486Ter

HGVS:

NC_000011.10:g.108330362C>T
NG_009830.1:g.112531C>T
NG_054724.1:g.144471G>A
NM_000051.4:c.7456C>TMANE SELECT
NM_001330368.2:c.641-21291G>A
NM_001351110.2:c.*38+4858G>A
NM_001351834.2:c.7456C>T
NP_000042.3:p.Arg2486Ter
NP_000042.3:p.Arg2486Ter
NP_001338763.1:p.Arg2486Ter
LRG_135t1:c.7456C>T
LRG_135:g.112531C>T
LRG_135p1:p.Arg2486Ter
NC_000011.9:g.108201089C>T
NM_000051.3:c.7456C>T
p.Arg2486Stop
p.R2486*

Protein change:

R2486*

Links:

dbSNP: rs587779865

NCBI 1000 Genomes Browser:

rs587779865

Molecular consequence:

NM_001330368.2:c.641-21291G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+4858G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7456C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.7456C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000547106	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23807571, 25614872, 12552559, 26681312, 27732944, 28724667, 28492532
SCV001361262	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 13, 2019)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 25525159, 12552559, 26681312, 21665257, 25122203, 29922827, 29667044, 28724667, 27732944, 30607632 Citation Link,
SCV002080632	Natera, Inc.	no assertion criteria provided	Pathogenic (Oct 1, 2021)	germline	clinical testing
SCV004009692	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 8, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004047252	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
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 (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000547106.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Arg2486*) 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 (rs587779865, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 12552559, 26681312, 27732944, 28724667). ClinVar contains an entry for this variant (Variation ID: 127445). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361262.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: ATM c.7456C>T (p.Arg2486X) 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 1.2e-05 in 251264 control chromosomes. c.7456C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Buzin_2003, Micol_2011, Meneret_2014). Heterozygous mutations in ATM are a risk allele for malignancies, and this mutation has also been reported in the literature in individuals with breast and other cancers (Takai_2016, Susswein_2016, Sun_2017, Ohmoto_2018, and Yang_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 submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/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., SCV002080632.1

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV004009692.1

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

Description

A heterozygous nonsense variant in exon 50 of the ATM gene that results in a stop codon and premature truncation of the protein at codon 2486 (p.Arg2486Ter) was detected. The observed variant has previously been reported in patients affected with ataxia telangiectasia [PMID: 25122203]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1) and gnomdAD (v2) databases and has a minor allele frequency of 0.0008% in the topmed database. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047252.1

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

Description

The stop gained c.7456C>T (p.Arg2486Ter) variant in ATM gene has been reported previously in homozygous state in patients affected with AtaxiaTelangiectasia (Buzin CH et al.,2003). This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. This variant has been submitted allele frequency 0.001194 % in the gnomAD and novel in 1000 genome database. The nucleotide change c.7456C>T in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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