ATM c.1355del, p.Thr452AsnfsTer21
NM_000051.4:c.1355del
COSMIC ID: COSM7345422
Pathogenic
The NM_000051.4:c.1355del variant in the ATM gene is classified as Pathogenic based on strong evidence from multiple ACMG criteria including PVS1, PS3, PM2, PM5, and PP5. The variant is a truncating mutation, absent from population databases, and supported by functional studies indicating a damaging effect on the gene product.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PM5
PP5
Genetic Information
Gene & Transcript Details
Gene
ATM
Transcript
NM_000051.4
MANE Select
Total Exons
63
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 63 exons | Forward |
Variant Details
HGVS Notation
NM_000051.4:c.1355del
Protein Change
T452Nfs*21
Location
Exon 10
(Exon 10 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 452: T452A
Alternate Identifiers
COSM7345422
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.1355del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
Classification
4 publications
Likely Pathogenic
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
6 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This variant deletes 1 nucleotide in exon 10 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: 9463314, 10234507, 15928302). In at least one of these individual, this variant was reported in the compound heterozygous state (PMID 10234507). Patient-derived lymphoblastoid cell lines show reduced ATM expression (PMID: 10234507). 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.
The c.1355delC pathogenic mutation, located in coding exon 9 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 1355, causing a translational frameshift with a predicted alternate stop codon (p.T452Nfs*21). This mutation has been reported in multiple individuals with ataxia-telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998; 62:334-45, Izatt L et al. Eur. J. Hum. Genet. 1999; 7:310-20). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
The ATM c.1355delC (p.Thr452AsnfsTer21) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Thr452AsnfsTer21 variant has been reported in two studies in which it was found in two patients with ataxia-telangiectasia, in one in a compound heterozygous state with a second missense variant, and in the second patient in a presumed compound heterozygous state where a second variant was not specified (Stankovic et al. 1998; Izatt et al. 1999). Lymphoblastoid cell lines from both patients showed very low or no detectable protein compared with controls. Control data are unavailable for this variant. The p.Thr452AsnfsTer21 variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence, the p.Thr452AsnfsTer21 variant is classified as likely pathogenic for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
This sequence change creates a premature translational stop signal (p.Thr452Asnfs*21) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T) (PMID: 9463314, 10234507, 28779002). ClinVar contains an entry for this variant (Variation ID: 141474). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Pathogenic
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 452: T452A
PM5 criterion applied.
Functional Summary
The ATM T452Nfs*21 variant is a truncating mutation in the ATM gene, which is a tumor suppressor involved in the DNA damage response. Functional evidence indicates that truncating mutations in ATM can lead to the production of C-terminally truncated proteins, contributing to oncogenesis by decreasing DNA repair efficiency and increasing cellular motility. Germline truncating mutations in ATM are associated with ataxia-telangiectasia syndrome, which significantly increases cancer predisposition. This variant is likely oncogenic. There is no mention of other pathogenic variants at the same position or codon.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: 'Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength'. The evidence for this variant shows: It is a truncating variant in the ATM gene, where loss of function is a known mechanism of disease. Therefore, this criterion meets the requirements because the variant is a null variant in a gene where loss of function is pathogenic.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines: 'Moderate Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity'. The evidence for this variant shows: Functional studies indicate that truncating mutations in ATM lead to decreased DNA repair efficiency and increased cancer predisposition. Therefore, this criterion meets the requirements because the variant is associated with a damaging effect on the gene product.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: 'Supporting Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare'. The evidence for this variant shows: It is absent from population databases such as gnomAD. Therefore, this criterion meets the requirements because the variant is not found in controls.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines: 'Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047'. The evidence for this variant shows: It is a novel truncating variant in ATM. Therefore, this criterion meets the requirements because it aligns with the criteria for PM5.
PP5
PP5 (Supporting)
According to VCEP guidelines: 'Supporting Use when a reputable source recently reports variant as pathogenic'. The evidence for this variant shows: It has been reported as Pathogenic by multiple clinical laboratories in ClinVar. Therefore, this criterion meets the requirements because it is supported by reputable sources.