NM_000051.4(ATM):c.513C>G (p.Tyr171Ter) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 31, 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:: RCV000533506.7

Allele description [Variation Report for NM_000051.4(ATM):c.513C>G (p.Tyr171Ter)]

NM_000051.4(ATM):c.513C>G (p.Tyr171Ter)

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.513C>G (p.Tyr171Ter)

HGVS:

NC_000011.10:g.108243969C>G
NG_009830.1:g.26138C>G
NM_000051.4:c.513C>GMANE SELECT
NM_001351834.2:c.513C>G
NP_000042.3:p.Tyr171Ter
NP_000042.3:p.Tyr171Ter
NP_001338763.1:p.Tyr171Ter
LRG_135t1:c.513C>G
LRG_135:g.26138C>G
LRG_135p1:p.Tyr171Ter
NC_000011.9:g.108114696C>G
NM_000051.3:c.513C>G
p.Y171*

Protein change:

Y171*

Links:

dbSNP: rs786201693

NCBI 1000 Genomes Browser:

rs786201693

Molecular consequence:

NM_000051.4:c.513C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001351834.2:c.513C>G - 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
SCV000622567	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23807571, 25614872, 9887333, 28492532
SCV000694299	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 29, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21778326, 9887333 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000795016	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Oct 24, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622567

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 31, 2023)

germline

clinical testing

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

SCV000694299

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 29, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000795016

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Oct 24, 2017)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
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 (5)

Details of each submission

From Invitae, SCV000622567.7

#	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.Tyr171*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333). ClinVar contains an entry for this variant (Variation ID: 184787). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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, SCV000694299.1

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

Description

Variant summary: The ATM c.513C>G (p.Tyr171X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g. p.Arg2506fsX3, p.Lys2756X). Mutation taster predicts a damaging outcome for this variant. This variant was absent in 43866 control chromosomes while it was found in at least one AT patient in homozygosity, indicating causality. In addition, a study reported ATM to be undetected in LCLs derived from an AT patient carying the variant of interest in homozygosity; these LCLs also had deregulated SSA and HDR, and were deficient in phosphorylation of SMC1, KAP1, and Chk2, further supporting pathogenicity. Moreover, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is 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 Counsyl, SCV000795016.1

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

#	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

Last Updated: Apr 15, 2024

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