NM_000051.4(ATM):c.2250+1G>A AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 3, 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:: RCV000702192.10

Allele description [Variation Report for NM_000051.4(ATM):c.2250+1G>A]

NM_000051.4(ATM):c.2250+1G>A

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.2250+1G>A

HGVS:

NC_000011.10:g.108256341G>A
NG_009830.1:g.38510G>A
NM_000051.4:c.2250+1G>AMANE SELECT
NM_001351834.2:c.2250+1G>A
LRG_135t1:c.2250+1G>A
LRG_135:g.38510G>A
NC_000011.9:g.108127068G>A
NM_000051.3:c.2250+1G>A

Links:

dbSNP: rs1565395193

NCBI 1000 Genomes Browser:

rs1565395193

Molecular consequence:

NM_000051.4:c.2250+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001351834.2:c.2250+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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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Nepeta teucriifolia isolate btd 1073 trnL-trnF intergenic spacer region, partial...
Nepeta teucriifolia isolate btd 1073 trnL-trnF intergenic spacer region, partial sequence; plastid
gi|2544235987|gb|OR199260.1|

Nucleotide
Pityriasis
Pityriasis
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MeSH
D010915 (1)
MeSH
H2A histone family, member B3 [Mus musculus]
H2A histone family, member B3 [Mus musculus]
gi|528078359|ref|NP_001268460.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000831036	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9887333, 10330348, 28492532
SCV004047449	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000831036

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

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

SCV004047449

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

germline

clinical testing

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

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D.

Hum Mol Genet. 1999 Jan;8(1):69-79.

PubMed [citation]

PMID:: 9887333

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

Teraoka SN, Telatar M, Becker-Catania S, Liang T, Onengüt S, Tolun A, Chessa L, Sanal O, Bernatowska E, Gatti RA, Concannon P.

Am J Hum Genet. 1999 Jun;64(6):1617-31.

PubMed [citation]

PMID:: 10330348
PMCID:: PMC1377904

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000831036.7

#	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 affects a donor splice site in intron 14 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 579018). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (Invitae). Other variant(s) that result in skipping of exon 14 have been determined to be pathogenic (PMID: 9887333, 10330348; Invitae). This suggests that this variant may also be clinically significant and likely 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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047449.1

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

Description

The c.2250+1G>A splice donor variant in ATM gene has been reported to the ClinVar database as Likely pathogenic. This variant has not been reported in the literature in individuals with ATM-related disease. The c.2250+1G>A variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has Donor and acceptor splice site variants typically lead to a loss of protein function (Baralle D, Baralle M., 2005). Loss-of-function variants in ATM are known to be pathogenic (Podralska et al., 2014; Huang et al., 2013). For these reasons, this variant has been classified as Likely 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: Oct 26, 2024

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