NM_000051.4(ATM):c.2880del (p.Leu961fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 8, 2022
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:: RCV000159629.11

Allele description [Variation Report for NM_000051.4(ATM):c.2880del (p.Leu961fs)]

NM_000051.4(ATM):c.2880del (p.Leu961fs)

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.2880del (p.Leu961fs)

HGVS:

NC_000011.10:g.108271105del
NG_009830.1:g.53274del
NM_000051.4:c.2880delMANE SELECT
NM_001351834.2:c.2880del
NP_000042.3:p.Leu961fs
NP_000042.3:p.Leu961fs
NP_001338763.1:p.Leu961fs
LRG_135t1:c.2880del
LRG_135:g.53274del
LRG_135p1:p.Leu961fs
NC_000011.9:g.108141829del
NC_000011.9:g.108141832del
NM_000051.3:c.2880del
NM_000051.3:c.2880delC
p.L961CfsX10

Protein change:

L961fs

Links:

dbSNP: rs730881300

NCBI 1000 Genomes Browser:

rs730881300

Molecular consequence:

NM_000051.4:c.2880del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.2880del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000581448	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 9, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10980530, 15196260, 26483394, 26681312 Citation Link,
SCV000905170	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10980530, 26483394, 26681312, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581448

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 9, 2020)

germline

clinical testing

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

Citation Link,

SCV000905170

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 8, 2022)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

The impact of an early truncating founder ATM mutation on immunoglobulins, specific antibodies and lymphocyte populations in ataxia-telangiectasia patients and their parents.

Stray-Pedersen A, Jónsson T, Heiberg A, Lindman CR, Widing E, Aaberge IS, Borresen-Dale AL, Abrahamsen TG.

Clin Exp Immunol. 2004 Jul;137(1):179-86.

PubMed [citation]

PMID:: 15196260
PMCID:: PMC1809075

Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.

Laake K, Jansen L, Hahnemann JM, Brondum-Nielsen K, Lönnqvist T, Kääriäinen H, Sankila R, Lähdesmäki A, Hammarström L, Yuen J, Tretli S, Heiberg A, Olsen JH, Tucker M, Kleinerman R, Børresen-Dale AL.

Hum Mutat. 2000 Sep;16(3):232-46.

PubMed [citation]

PMID:: 10980530

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000581448.6

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

Description

The c.2880delC pathogenic mutation, located in coding exon 18 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 2880, causing a translational frameshift with a predicted alternate stop codon (p.L961Cfs*10). This alteration has been detected in the compound heterozygous state in two Norwegian individuals with ataxia-telangiectasia (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Stray-Pedersen A et al. Clin. Exp. Immunol. 2004 Jul;137:179-86). This alteration has also been reported in a breast cancer patient and a pancreatic cancer patient who underwent hereditary cancer multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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 Color Diagnostics, LLC DBA Color Health, SCV000905170.4

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

Description

This variant deletes 1 nucleotide in exon 19 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 10980530), breast cancer (PMID: 26681312), and pancreatic cancer (PMID: 26483394). This variant has been identified in 1/251426 chromosomes 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 13, 2025

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