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
OpenFunctional Impact & Domains
Functional Domain
The ATM F2799Kfs*4 variant is a truncating mutation in the ATM gene, which is a tumor suppressor involved in the DNA damage response. Functional studies indicate that truncating mutations in ATM can lead to the production of C-terminally truncated proteins, resulting in decreased DNA repair efficiency and increased cellular motility. These effects support the conclusion that the ATM F2799Kfs*4 variant is likely oncogenic.
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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 leading to a premature stop codon (F2799Kfs*4), predicted to undergo NMD in a gene where LOF is a known disease mechanism and not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP gene-specific decision tree for truncating variants in ATM.
PS1 (Not Applied)
According to standard ACMG guidelines: PS1 applies when the same amino acid change as a known pathogenic variant is observed. The evidence for this variant shows a novel frameshift rather than a known missense change. Therefore, PS1 is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines: PS2 applies for confirmed de novo occurrence with maternity and paternity confirmed. No parental testing data are available for this variant. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to VCEP guidelines: PS3 requires functional rescue assays specific to ATM, with moderate strength if both target phosphorylation and radiosensitivity rescue fail, or supporting strength if only phosphorylation rescue fails. The evidence describes generic truncation effects without rescue experiments. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines: PS4 applies when there is significant statistical evidence from case-control studies (OR ≥2, p≤0.05). No case-control data are provided. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines: PM1 applies to variants located in mutational hot spots or critical functional domains. No domain or hotspot information is provided for this residue. Therefore, PM1 is not applied.
PM2 (Not Applied)
According to VCEP guidelines: PM2_Supporting applies for frequency ≤0.001% if n=1. The evidence shows MAF=0.00199% (5/251232 alleles), above the VCEP threshold. Therefore, PM2 is not applied.
PM3 (Not Applied)
According to VCEP guidelines: PM3 applies to recessive disorders when a variant is detected in trans with a pathogenic variant. No allelic configuration data are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines: PM4 applies to protein length changes due to in-frame indels or stop-loss variants. This is a frameshift leading to stop gain, which is covered by PVS1, not PM4. Therefore, PM4 is not applied.
PM5 (Supporting)
According to VCEP guidelines: PM5_Supporting applies to truncating variants with PTC upstream of p.R3047. The variant F2799Kfs*4 introduces a stop codon upstream of p.R3047. Therefore, PM5 is applied at Supporting strength as per gene-specific rule.
PM6 (Not Applied)
According to standard ACMG guidelines: PM6 applies to assumed de novo variants without confirmation of maternity/paternity. No de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines: PP1 applies with segregation data. No family segregation information is provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines: PP2 applies to missense variants in genes with low benign missense variation. This is a truncating variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines: PP3 applies when REVEL >0.7333 or strong splicing prediction. No REVEL score or significant splicing impact is present. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines: PP4 applies when patient phenotype is highly specific for a single gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines: PP5 applies when a reputable source classifies the variant as pathogenic. The variant is not found in ClinVar or other databases. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines: BA1 applies for allele frequency >5%. The observed MAF is 0.00199%. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines: BS1 applies for allele frequency >1% (disease-specific threshold). The MAF is well below that. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines: BS2 applies when observed in healthy individuals. No such data are reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines: BS3 applies when variant rescues ATM-specific functional assays. No rescue data are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines: BS4 applies for lack of segregation in affected family members. No non-segregation data exist. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines: BP1 applies to missense variants in a gene where only LOF causes disease. This is a LOF variant. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines: BP2 applies to variants in trans with a pathogenic variant in recessive disease. No such data. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. This is a frameshift. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines: BP4 applies when REVEL ≤0.249 or benign splice prediction. No computational benign evidence is available. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines: BP5 applies when variant found in a case with an alternate molecular cause. No alternate cause has been documented. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines: BP6 applies when a reputable source classifies the variant as benign. No such assertion exists. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines: BP7 applies to synonymous or deep intronic variants with no splicing impact. This is a frameshift. Therefore, BP7 is not applied.