NM_000051.3(ATM):c.2839-579_2839-576del AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 7, 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:: RCV001016574.6

Allele description [Variation Report for NM_000051.3(ATM):c.2839-579_2839-576del]

NM_000051.3(ATM):c.2839-579_2839-576del

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.3(ATM):c.2839-579_2839-576del

HGVS:

NC_000011.10:g.108270485_108270488del
NG_009830.1:g.52654_52657del
NM_000051.4:c.2839-579_2839-576delMANE SELECT
NM_001351834.2:c.2839-579_2839-576del
LRG_135t1:c.2839-579_2839-576del
LRG_135:g.52654_52657del
NC_000011.9:g.108141210_108141213del
NC_000011.9:g.108141212_108141215del
NM_000051.3:c.2839-579_2839-576del
NM_000051.3:c.2839-579_2839-576delAAGT

Note:

NCBI staff reviewed the sequence information reported in PubMed 11889466 to determine the location of this deletion on the current reference sequence. The 4-nt intronic deletion in IVS18 (IVS20 in PubMed 11889466) causes the activation of a cryptic 65-nt exon in gene ATM.

Links:

OMIM: 607585.0026; dbSNP: rs587776552

NCBI 1000 Genomes Browser:

rs587776552

Molecular consequence:

NM_000051.4:c.2839-579_2839-576del - intron variant - [Sequence Ontology: SO:0001627]
NM_001351834.2:c.2839-579_2839-576del - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001177540	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11889466, 12815592, 14695534, 19773425, 9887333 Citation Link,
SCV002532885	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Jun 27, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 11889466, 9887333, 14695534, 19773425 Citation Link,
SCV004361578	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11889466, 12815592, 14695534, 19773425, 22213089, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001177540

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 22, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002532885

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Jun 27, 2021)

germline

curation

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

Citation Link,

SCV004361578

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 7, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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, curation

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

A new type of mutation causes a splicing defect in ATM.

Pagani F, Buratti E, Stuani C, Bendix R, Dörk T, Baralle FE.

Nat Genet. 2002 Apr;30(4):426-9. Epub 2002 Mar 11.

PubMed [citation]

PMID:: 11889466

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV001177540.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.2839-579_2839-576delAAGT intronic pathogenic mutation, located in intron 17 of the ATM gene, results from a deletion of 4 nucleotides within intron 17 of the ATM gene. This variant has been identified in multiple patients with Ataxia Telangiectasia in a compound heterozygous state with other pathogenic ATM variants; cell lines derived from these patients showed radiosensitivity and low or no detectable ATM protein (Mitui M et al. Hum. Mutat., 2003 Jul;22:43-50; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76; Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Pastor T et al. Nucleic Acids Res., 2009 Nov;37:7258-67). This variant results in the inclusion of 65 nucleotides of intron 17 leading to a predicted frameshift and premature termination codon (Pagani F et al. Nat. Genet., 2002 Apr;30:426-9; Eng L et al. Hum. Mutat., 2004 Jan;23:67-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Sema4, Sema4, SCV002532885.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

#	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 Color Diagnostics, LLC DBA Color Health, SCV004361578.1

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

Description

This variant causes a 4 base-pair deletion in intron 18 of the ATM gene and is described in the literature as 'a deletion of 4 bp (GTAA) in intron 20' (numbering based on the U33841 transcript) and 'IVS20-579del-AAGT'. RNA studies have shown that this variant disrupts a non-canonical U1 small nuclear ribonucleoprotein binding site resulting in the insertion of a 65 base-pair cryptic exon, which is predicted to cause a frameshift and premature stop codon (PMID: 11889466, 12815592, 14695534, 19773425). An allele-specific RT-PCR assay using cells from a carrier individual has shown that the mutant allele does not produce normal transcript (PMID: 11889466). This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 11889466, 12815592, 14695534, 22213089). Lymphoblastoid cell lines derived from two of these individuals showed radiosensitivity and a significant reduction in protein expression (PMID: 14695534). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, 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

Last Updated: Jan 19, 2025

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