ATM c.1355del, p.Thr452AsnfsTer21

NM_000051.4:c.1355del

COSM7345422

Classification Summary

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.

Population Frequency

0.0 in 100,000

Rare

ClinVar Classification

Likely Pathogenic

4 publications

REVEL Score

N/A

Not Available

COSMIC Recurrence

1 occurrences

No Criteria Applied

Classification Evidence

Very Strong (PVS)

PVS1

Strong (PS/BS)

None applied

Moderate (PM/BA)

PS3

Supporting (PP/BP)

PM2 PM5 PP5

ClinVar COSMIC OncoKB JAX-CKB SpliceAI

Created: 2025-04-04T13:33:21.496373

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

ATM

Transcript

                                        
                                            NM_000051.4
                                        
                                                    MANE Select

Total Exons

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

Clinical Evidence

Population Frequency

Global Frequency

0.0 in 100,000

Extremely Rare

Global: 0.0%

0.0005%

0.001%

0.01%

0.05%

1%+

ACMG Criteria Applied

PM2

This variant is rare in the population (0.000000% MAF).

ClinVar 2025-04-04T13:33:21.495643

Classification

4 publications

Likely Pathogenic

Based on 7 submitter reviews in ClinVar

Submitter Breakdown

6 Path

1 LP

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

4 publications

Show publication details

PMID: 9463314

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.

PMID: 10234507

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.

PMID: 9463314

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.

PMID: 23807571

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.

Publication Summary:

- **9463314**: This variant deletes one nucleotide in the ATM gene, causing a frameshift and premature stop signal, leading to a non-functional protein. It has been reported in individuals with ataxia-telangiectasia, including in a compound heterozygous state. Patient-derived cell lines show reduced ATM expression. - **10234507**: The variant is associated with ataxia-telangiectasia and has been observed in a compound heterozygous state. It results in reduced ATM protein expression in patient-derived cell lines. - **15928302**: The variant has been reported in individuals with ataxia-telangiectasia, contributing to the pathogenic classification. - **11821961**: The variant is a frameshift mutation leading to protein truncation, associated with ataxia-telangiectasia, and is considered pathogenic by clinical consortia. - **28152038**: This frameshift variant is linked to protein truncation and is considered pathogenic due to its absence in population cohorts and its association with disease. - **28779002**: The variant is linked to ataxia-telangiectasia and is not present in population databases, supporting its pathogenic classification. - **31948886**: The variant is a frameshift mutation leading to protein truncation, considered pathogenic due to its absence in population cohorts. - **26896183**: The variant is associated with ataxia-telangiectasia and is absent from population databases, supporting its pathogenic classification. - **35154108**: The variant is a frameshift mutation leading to protein truncation, considered pathogenic due to its absence in population cohorts. - **32694154**: The variant is a frameshift mutation leading to protein truncation, considered pathogenic due to its absence in population cohorts. - **35365198**: The variant is a frameshift mutation leading to protein truncation, considered pathogenic due to its absence in population cohorts. - **34887416**: The variant is a frameshift mutation leading to protein truncation, considered pathogenic due to its absence in population cohorts. - **23807571**: The variant creates a premature stop signal in the ATM gene, leading to a non-functional protein. Loss-of-function variants in ATM are known to be pathogenic. - **25614872**: The variant creates a premature stop signal in the ATM gene, leading to a non-functional protein. Loss-of-function variants in ATM are known

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

COSMIC

COSMIC ID

COSM7345422

Recurrence

1 occurrences

PM1 Criteria

Not Applied

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Functional Domain

Cancer Hotspots

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: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Functional Studies

Functional Impact

OncoKB JAX-CKB

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 Evidence

Pathogenicity Predictions

Predictor Consensus

Unknown

PP3 Applied

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.0	-118 bp
- Donor Loss	0.02	76 bp
+ Acceptor Gain	0.0	-111 bp
+ Donor Gain	0.02	-66 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria 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.

LYFE SCIENCES

ATM c.1355del, p.Thr452AsnfsTer21

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines