Genetic Information

Gene & Transcript Details

Gene
ATM
Transcript
NM_000051.4 MANE Select
Total Exons
—
Reference Sequence
NC_000011.9
Alternative Transcripts
IDStatusDetails
NM_000051.3 RefSeq Select 13147 nt | 386–9556
NM_000051.4 MANE Select 12915 nt | 151–9321

Variant Details

HGVS Notation
NM_000051.4:c.8052_8055del
Protein Change
Q2684Hfs*8
Location
Exon 55 (Exon 55 of )
55
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.0 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Pathogenic
1 publications
Publications List
PMID: 23807571

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant has not been reported in the literature in individuals with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln2684Hisfs*8) in the ATM gene. It is expected to result in an absent or disrupted protein product.

Clinical Statement

"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."

COSMIC Somatic Evidence

Open
COSMIC ID
Recurrence
0 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
COSMIC Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene ATM.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: ATMQ2684Hfs*8ATMQ2684Hfs*8SomaticNCBI Gene:472|Show additional gene information Variant OverviewATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.The ATM Q2684Hfs*8 is a truncating mutation in a tumor suppressor gene, and therefore is likely oncogenic.Hide mutation effect description The mutation effect description for truncating mutations in ATM is: ATM truncating mutations can produce several forms of C-terminally truncated ATM proteins. When found in the germline, these mutations result in ataxia-telangiectasia syndrome, which increases cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers (PMID: 27413114). Deletion of ATM in mouse models and cell lines demonstrates that it is oncogenic as measured by decreased DNA repair efficiency and increased cellular motility (PMID: 30553448, 30348496). JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Unknown
PP3 Applied
No
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.0 416 bp
- Donor Loss (DL) 0.0 34 bp
+ Acceptor Gain (AG) 0.0 -25 bp
+ Donor Gain (DG) 0.01 -9 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PVS1

PVS1 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PS3

PS3 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PP5

PP5 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)