NM_000051.4(ATM):c.5511_5512del (p.Phe1837fs) AND Ataxia-telangiectasia syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Apr 26, 2019
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:: RCV000550809.6

Allele description

NM_000051.4(ATM):c.5511_5512del (p.Phe1837fs)

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.5511_5512del (p.Phe1837fs)

HGVS:

NC_000011.10:g.108304689_108304690del
NC_000011.9:g.108175414_108175415del
NG_009830.1:g.86858_86859del
NM_000051.4:c.5511_5512delMANE SELECT
NM_001351834.2:c.5511_5512del
NP_000042.3:p.Phe1837fs
NP_001338763.1:p.Phe1837fs
LRG_135:g.86858_86859del
NC_000011.9:g.108175414_108175415del
NC_000011.9:g.108175414_108175415delTT
NC_000011.9:g.108175416_108175417del
NM_000051.3:c.5511_5512delTT
NM_000051.4:c.5511_5512del

Protein change:

F1837fs

Links:

dbSNP: rs1555107263

NCBI 1000 Genomes Browser:

rs1555107263

Molecular consequence:

NM_000051.4:c.5511_5512del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.5511_5512del - 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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Homo sapiens RAD51 homolog C (S. cerevisiae), mRNA (cDNA clone IMAGE:7939775), c...
Homo sapiens RAD51 homolog C (S. cerevisiae), mRNA (cDNA clone IMAGE:7939775), complete cds
gi|62739821|gb|BC093930.1|

Nucleotide
cullin-4B isoform X3 [Canis lupus familiaris]
cullin-4B isoform X3 [Canis lupus familiaris]
gi|1953104296|ref|XP_038444145.1|

Protein
putative polygalacturonase (PGA3) [Arabidopsis thaliana]
putative polygalacturonase (PGA3) [Arabidopsis thaliana]
gi|20465449|gb|AAM20184.1|

Protein
Catostomidae interphotoreceptor retinoid-binding protein 2 (IRBP2) gene, partial...
Catostomidae interphotoreceptor retinoid-binding protein 2 (IRBP2) gene, partial cds.
PopSet: 325112630

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Bodily distress disorder
Bodily distress disorder

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000622597	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 12, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25614872, 23807571, 28492532
SCV001360468	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 26, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000622597

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 12, 2017)

germline

clinical testing

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

SCV001360468

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 26, 2019)

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

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

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000622597.4

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

Description

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). This sequence change deletes 2 nucleotides from exon 37 of the ATM mRNA (c.5511_5512delTT), causing a frameshift at codon 1837. This creates a premature translational stop signal (p.Phe1837Leufs*11) and is expected to result in an absent or disrupted protein product.

#	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, SCV001360468.1

#	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.5511_5512delTT (p.Phe1837LeufsX11) 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 (e.g. c.5712dupA (p.Ser1905fsX25), c.5908C>T (p.Gln1970X), c.6404_6405insTT (p.Arg2136fsX1)). The variant was absent in 250904 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5511_5512delTT in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as 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 16, 2024

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