Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000051.3 | RefSeq Select | 13147 nt | 386–9556 |
| NM_000051.4 | MANE Select | 12915 nt | 151–9321 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The ATM F2799Kfs*4 variant is a truncating mutation in the ATM gene, which is involved in the DNA damage response. Functional evidence indicates that truncating mutations in ATM can lead to the production of C-terminally truncated ATM proteins. These mutations are associated with decreased DNA repair efficiency and increased cellular motility, supporting a damaging effect. Additionally, deletion of ATM in experimental models has demonstrated oncogenic properties.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 141 bp |
| Donor Loss (DL) | 0.0 | -55 bp |
| Acceptor Gain (AG) | 0.02 | -115 bp |
| Donor Gain (DG) | 0.07 | 34 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows a frameshift c.8395_8404del (F2799Kfs*4) resulting in a premature termination codon and predicted loss‐of‐function in ATM, where LOF is a known mechanism and the variant is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the gene‐specific null variant criteria.
PS1 (Not Applied)
According to standard ACMG guidelines, PS1 is: "Same amino acid change as a previously established pathogenic variant." The evidence for this variant shows a novel frameshift rather than a known identical amino acid substitution. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No parental testing or de novo data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines, PS3 requires functional rescue assays for ATM: strong evidence must be downgraded and moderate/supporting strengths require specific rescue data. The available studies demonstrate loss of function but do not include the required rescue experiments. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (case-control data)." No case-control or statistical data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." This frameshift is not in a defined functional domain beyond causing LOF. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines, PM2_supporting is: "Frequency ≤0.001% if n=1 in a single subpopulation." The observed MAF is 0.00199% in gnomAD. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to VCEP guidelines, PM3 pertains to observations in trans with a pathogenic variant in recessive disease. No allelic or trans data are available for this variant. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." This is a frameshift leading to truncation, not an in-frame deletion or stop-loss. Therefore, PM4 is not applied.
PM5 (Supporting)
According to VCEP guidelines, PM5_supporting is: "Supporting Strength: Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047." The variant introduces a premature stop at codon 2803, which is upstream of p.R3047. Therefore, PM5 is applied at Supporting strength.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." No de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, PP1 is: "Co-segregation with disease in multiple affected family members." No segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 is: "Missense variant in a gene with low rate of benign missense variation." This is not a missense variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 is: "Supporting: REVEL >.7333 or splicing prediction impact." Computational predictions for splicing (SpliceAI 0.07) and protein effect are insufficient. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype or clinical correlation data provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 is: "Reputable source reports variant as pathogenic without available evidence." This variant is not in ClinVar. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 is: "Stand Alone Filtering Allele Frequency >0.5%." The observed allele frequency (0.00199%) is far below this threshold. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 is: "Strong Filtering Allele Frequency >0.05%." The observed allele frequency (0.00199%) is below this threshold. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, BS2 is: "Observed in a healthy adult individual for a recessive (homozygous) or dominant (heterozygous) condition." No such data are available. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional rescue of ATM-specific features. No rescue data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, BS4 is: "Lack of segregation in affected members of a family." No segregation data available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 is: "Missense variant in a gene where only loss-of-function causes disease." This is a loss-of-function variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 pertains to cis/trans observations with pathogenic variants. No such data are available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 is: "In-frame deletions/insertions in repetitive regions." This is a frameshift deletion. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 is: "Supporting: REVEL ≤.249 or no splicing impact predicted." Computational evidence does not support benign interpretation. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 is: "Variant found in a case with an alternate molecular basis for disease." No alternate cause reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 is: "Reputable source reports variant as benign without evidence." No such reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 is: "Synonymous variant with no predicted splice impact." This is not a synonymous variant. Therefore, BP7 is not applied.