ATM c.8395_8404del, p.Phe2799LysfsTer4
NM_000051.4:c.8395_8404del
COSMIC ID: COSM6213119
Pathogenic
This ATM frameshift variant (F2799Kfs*4) meets gene-specific PVS1 at Very Strong and PM5 at Supporting. No other criteria apply under VCEP rules. This evidence supports a Likely Pathogenic classification due to LOF mechanism and truncation upstream of the critical region.
ACMG/AMP Criteria Applied
PVS1
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.8395_8404del
Protein Change
F2799Kfs*4
Location
Exon 57
(Exon 57 of 63)
5'Exon Structure (63 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2799: F2799V
Alternate Identifiers
COSM6213119
Variant interpretation based on transcript NM_000051.4
Genome Browser
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HGVS InputNM_000051:c.8395_8404del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00199%
Rare
Highest in Population
Remaining individuals
0.0163%
Low Frequency
Global: 0.00199%
Remaining individuals: 0.0163%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251232Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00199%, 5/251232 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0163%, 1/6128 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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
ClinVar reports other pathogenic variants at position 2799: F2799V
PM5 criterion applied.
Functional Summary
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.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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 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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Not Applied) Strength Modified
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
PM2 (Not Applied) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Supporting) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP1 applies with segregation data. No family segregation information is 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 benign missense variation. This is a truncating variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BA1 applies for allele frequency >5%. The observed MAF is 0.00199%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: BS2 applies when observed in healthy individuals. No such data are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 applies when variant rescues ATM-specific functional assays. No rescue data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP3 applies to in-frame indels in repetitive regions. This is a frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.