ATM c.5807T>G, p.Leu1936Ter
NM_000051.4:c.5807T>G
Pathogenic
The ATM L1936* truncating variant meets VCEP criteria PVS1_Very Strong for LOF, PM2_Supporting for absence in population databases, and PM5_Supporting for a premature stop codon upstream of p.R3047. In combination, these criteria yield a Likely Pathogenic classification under ACMG/VCEP guidelines.
ACMG/AMP Criteria Applied
PVS1
PM2
PM5
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.5807T>G
Protein Change
L1936*
Location
Exon 39
(Exon 39 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.5807T>G
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 not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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
Functional Summary
The ATM L1936* variant is a truncating mutation in a tumor suppressor gene, likely resulting in loss of function. Functional studies indicate that truncating mutations in ATM can lead to decreased DNA repair efficiency and increased cellular motility, supporting a damaging effect. This variant has been associated with oncogenic processes in various cancer types.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 8.86
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree." The evidence for this variant shows a premature stop codon (L1936*) in ATM, predicted to undergo NMD, and LOF is a known mechanism of disease in ATM. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant. This variant is a nonsense change and does not meet PS1 criteria. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. No de novo data are provided. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity, and PS3 Supporting requires failure to rescue an ATM-specific feature alone. No rescue assay data are available. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires statistical evidence from case-control studies. No case-control data are provided. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical domains. There is no evidence that this truncating variant lies in a specific mutational hot spot beyond LOF mechanism. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting applies for allele frequency ≤0.001% in population databases. The evidence for this variant shows absence from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength due to absence in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to detection of variants in trans in recessive disorders. No trans allele data are provided and ATM cancer predisposition is not assessed by PM3. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to in‐frame deletions/insertions or stop‐loss variants. This is a stop‐gain (nonsense) variant. Therefore, PM4 is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, PM5 Supporting applies to truncating variants with PTC upstream of p.R3047. The evidence for this variant shows a PTC at codon 1936, which is upstream of codon 3047. Therefore, PM5 is applied at Supporting strength.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires co‐segregation with disease in multiple affected family members. No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low rate of benign missense changes. This is a nonsense variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 Supporting requires REVEL >0.7333 or splicing impact by a well‐established predictor. Computational evidence here does not meet these thresholds. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype for a single gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 requires a reputable source reporting the variant as pathogenic. No such report is available. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 requires allele frequency >5% in general population. The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 requires allele frequency greater than expected for disorder. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 requires observation of the variant in healthy individuals. No such data are provided. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 Moderate/Supporting requires rescue of ATM-specific features and/or radiosensitivity. No rescue data are provided. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires non-segregation in affected family members. No segregation data are provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only truncating variants cause disease. This is a truncating variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observed in cis with a pathogenic variant in recessive disorders. Not applicable here. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions. Not applicable. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires benign computational evidence (REVEL ≤0.249 or splicing). Computational data are mixed and do not meet VCEP thresholds. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in a case with an alternate molecular basis for disease. No such alternate basis is provided. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a variant is reported as benign by a reputable source without available evidence. No such report is available. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or deep intronic variants with no splice impact. This is a nonsense variant. Therefore, BP7 is not applied.