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.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.2880del (p.Leu961fs)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000051.4(ATM):c.2880del (p.Leu961fs)
Variation ID: 181871 Accession: VCV000181871.24
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 108271102 (GRCh38) [ NCBI UCSC ] 11: 108141829 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 6, 2017 May 1, 2024 Jan 18, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.2880del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Leu961fs frameshift NM_000051.3:c.2880delC NM_001351834.2:c.2880del NP_001338763.1:p.Leu961fs frameshift NC_000011.10:g.108271105del NC_000011.9:g.108141832del NG_009830.1:g.53274del LRG_135:g.53274del LRG_135t1:c.2880del LRG_135p1:p.Leu961fs - Protein change
- L961fs
- Other names
- -
- Canonical SPDI
- NC_000011.10:108271101:CCCC:CCC
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| ATM | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
10842 | 17443 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2022 | RCV000159629.11 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 25, 2023 | RCV000412201.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 15, 2018 | RCV000497266.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 18, 2024 | RCV004019932.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000581448.6
First in ClinVar: Feb 24, 2015 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000905170.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Sep 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000622373.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) in the ATM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) 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 present in population databases (rs758561876, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and pancreatic cancers (PMID: 10980530, 17376192, 26483394, 26681312). ClinVar contains an entry for this variant (Variation ID: 181871). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004933430.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Nov 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000209616.5
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that … (more)
This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]TTGC. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 961 and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.2880delC has been reported in a compound heterozygous state in individuals with ataxia telangiectasia (Laake 2000, Stray-Pedersen 2004), as well as in an individual with pancreatic cancer (Hu 2016). We therefore consider this variant to be pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 30, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486873.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 29, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002076459.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
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.
Comment:
This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) 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 present in population databases (rs758561876, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and pancreatic cancers (PMID: 10980530, 17376192, 26483394, 26681312). ClinVar contains an entry for this variant (Variation ID: 181871). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]TTGC. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 961 and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.2880delC has been reported in a compound heterozygous state in individuals with ataxia telangiectasia (Laake 2000, Stray-Pedersen 2004), as well as in an individual with pancreatic cancer (Hu 2016). We therefore consider this variant to be pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
This sequence change creates a premature translational stop signal (p.Leu961Cysfs*10) 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 present in population databases (rs758561876, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and pancreatic cancers (PMID: 10980530, 17376192, 26483394, 26681312). ClinVar contains an entry for this variant (Variation ID: 181871). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This pathogenic variant is denoted ATM c.2880delC at the cDNA level and p.Leu961CysfsX10 (L961CfsX10) at the protein level. The normal sequence, with the base that is deleted in brackets, is ACCC[delC]TTGC. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 961 and creates a premature stop codon at position 10 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.2880delC has been reported in a compound heterozygous state in individuals with ataxia telangiectasia (Laake 2000, Stray-Pedersen 2004), as well as in an individual with pancreatic cancer (Hu 2016). We therefore consider this variant to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients. | Hu C | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2016 | PMID: 26483394 |
| Ten new ATM alterations in Polish patients with ataxia-telangiectasia. | Podralska MJ | Molecular genetics & genomic medicine | 2014 | PMID: 25614872 |
| Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. | Huang Y | Neuromolecular medicine | 2013 | PMID: 23807571 |
| Ocular findings in Norwegian patients with ataxia-telangiectasia: a 5 year prospective cohort study. | Riise R | Acta ophthalmologica Scandinavica | 2007 | PMID: 17376192 |
| 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 | Clinical and experimental immunology | 2004 | PMID: 15196260 |
| Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. | Laake K | Human mutation | 2000 | PMID: 10980530 |
Text-mined citations for rs730881300 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.