About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.8395_8404del, p.(Phe2799LysfsTer4)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen ATM VCEP v1.5.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
ATM HBOP VCEP v1.5 allows PVS1 via the ATM decision tree for null variants. NM_000051.4:c.8395_8404del is an exonic frameshift with predicted protein consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4); the event is upstream of the ATM truncation boundary referenced in the specification and there is no evidence from SpliceAI of an alternate splice mechanism that would replace the expected loss-of-function interpretation.
PM5Supporting
PM5 · supporting
ATM HBOP VCEP specifies PM5_Supporting for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a stop at codon 2802, which is upstream of p.Arg3047.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ATM HBOP VCEP v1.5 ACMG/AMP specification; applied evidence PVS1_VeryStrong + PM5_Supporting (Bayesian point total verified from applied evidence = 9).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 9 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
ATM HBOP VCEP v1.5 supports PVS1 for null variants through the ATM PVS1 decision tree, and this variant is an exonic frameshift with predicted consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4).
ATM-specific PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047; this variant truncates at codon 2802, upstream of that boundary.
PM2 was not applied because gnomAD v4 shows 20/1613922 alleles (0.00124%), slightly above the ATM PM2_Supporting threshold of 0.001%.
ClinVar contains a concordant ClinGen HBOP expert-panel Pathogenic classification for this variant, but that assertion was treated as contextual support rather than as a standalone ACMG criterion.
No criteria match.
Met · 2
PVS1 Very strongATM HBOP VCEP v1.5 allows PVS1 via the ATM decision tree for null variants. NM_000051.4:c.8395_8404del is an exonic frameshift with predicted protein consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4); the event is upstream of the ATM truncation boundary referenced in the specification and there is no evidence from SpliceAI of an alternate splice mechanism that would replace the expected loss-of-function interpretation. Details ▾Hide ▴
Rule
Use ATM PVS1 Decision Tree
Evidence considered
- Frameshift in ATM
- Predicted protein: p.(Phe2799LysfsTer4)
- SpliceAI max delta 0.07
Sources
PM5 SupportingATM HBOP VCEP specifies PM5_Supporting for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a stop at codon 2802, which is upstream of p.Arg3047. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.
Evidence considered
- Protein consequence p.(Phe2799LysfsTer4) terminates before p.Arg3047
Sources
Not met · 3 · evaluated, threshold not reached
PM2 ATM PM2 is downgraded to PM2_Supporting and requires frequency <=0.001% in gnomAD v4. This variant is present at 20/1613922 alleles (0.00124%), so the ATM threshold is not met. Details ▾Hide ▴
Rule
Frequency <=0.001% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 total AF 1.2392172608093824e-05 (0.00124%)
- No homozygotes observed
Sources
BA1 The gnomAD v4 frequency is far below the ATM BA1 stand-alone threshold (>0.5%). Details ▾Hide ▴
Rule
Grpmax Filtering AF >.5% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 total AF 0.00124%
Sources
BS1 The gnomAD v4 frequency is far below the ATM BS1 threshold (>0.05%). Details ▾Hide ▴
Rule
Grpmax Filtering AF >.05% in gnomAD v4 dataset
Evidence considered
- gnomAD v4 total AF 0.00124%
Sources
Not assessed · 9 · no assessment recorded
PS1 No same-amino-acid or same-splicing-event reference variant evidence was extracted in the workspace for PS1 assessment. Details ▾Hide ▴
Rule
Use for missense changes with same amino acid change, or ATM PS1 splicing table for same predicted splice event.
Still missing
- No variant-specific PS1 table lookup result was present in the assembled workspace.
Sources
cspec ↗vcep_a_t_m___p_s_1___1___5
PS3 The workspace contains ATM functional-framework materials, but no curated variant-specific rescue/failure-to-rescue data for c.8395_8404del were extracted for direct PS3 use. Details ▾Hide ▴
Rule
Moderate: fails to rescue both ATM-specific feature and radiosensitivity; Supporting: fails to rescue ATM-specific feature only.
Evidence considered
- Functional literature packet reviewed at abstract/theme level only
Still missing
- No variant-specific functional assay result was extracted from the cited literature packet.
Sources
PS4 The workspace did not provide a case-control analysis satisfying the ATM PS4 rule. Existing literature citations and ClinVar submissions indicate prior observations, but the needed odds ratio/risk estimate was not extracted for independent PS4 assignment. Details ▾Hide ▴
Rule
Case-control studies; p-value <=.05 and OR/HR/RR >=2 or lower 95% CI >=1.5.
Evidence considered
- ClinVar expert-panel and clinical-laboratory observations exist
Still missing
- No case-control estimate meeting the ATM PS4 threshold was extracted.
Sources
PM3 ATM PM3 requires proband-level recessive evidence with phase/zygosity scoring. The workspace did not extract proband-specific in-trans or homozygous observations for this variant. Details ▾Hide ▴
Rule
Assign PM3 strength based on summed points from the ATM PM3/BP2 table.
Still missing
- No explicit PM3 point tally for c.8395_8404del was present.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5
PP1 No family segregation data were extracted for affected relatives with biallelic ATM variants, so PP1 was not applied. Details ▾Hide ▴
Rule
AR condition: segregation in 1/2/>=3 affected relatives for supporting/moderate/strong.
Still missing
- No segregation pedigree data in the workspace.
Sources
PP3 PP3 is not applied. The variant is not a missense change, SpliceAI does not predict splice impact (max delta 0.07), and the ATM specification notes splice-prediction PP3 should not be added on top of PVS1-based loss-of-function interpretation. Details ▾Hide ▴
Rule
Missense REVEL >.7333 or splicing SpliceAI >=0.2
Evidence considered
- SpliceAI max delta 0.07
Sources
BS3 No variant-specific evidence showing rescue of ATM-specific function or radiosensitivity was extracted for this allele, so BS3 was not applied. Details ▾Hide ▴
Rule
Moderate: rescues both ATM-specific feature and radiosensitivity; Supporting: rescues either one.
Evidence considered
- Functional literature packet reviewed at abstract/theme level only
Still missing
- No variant-specific benign functional rescue data were extracted in the workspace.
Sources
BP2 ATM BP2 also requires proband-level co-occurrence/phase information in unaffected individuals; no such evidence was extracted in the workspace. Details ▾Hide ▴
Rule
Assign BP2 strength based on summed negative points from the ATM PM3/BP2 table.
Still missing
- No explicit BP2 point tally for c.8395_8404del was present.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5
BP4 SpliceAI shows no significant splice impact (max delta 0.07), but BP4 is not used here because the variant is an obvious frameshift loss-of-function allele and splice-only benign computational evidence does not address the primary predicted protein-damaging mechanism. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI <=0.1).
Evidence considered
- SpliceAI max delta 0.07
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AATM HBOP VCEP states PS2 is not used for ATM. Details ▾Hide ▴
PM1 N/AATM HBOP VCEP states PM1 should not be used because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined. Details ▾Hide ▴
PM4 N/AATM PM4 is reserved for stop-loss variants and not for this frameshift deletion. Details ▾Hide ▴
PM6 N/AATM HBOP VCEP states PM6 is not used for ATM. Details ▾Hide ▴
PP2 N/AATM HBOP VCEP states PP2 should not be used because ATM does not have a defined low rate of benign missense variation. Details ▾Hide ▴
PP4 N/AATM HBOP VCEP states PP4 should not be used for ATM in either the dominant cancer setting or as a separate line for A-T because phenotype evidence is already built into the PM3/BP2 framework. Details ▾Hide ▴
PP5 N/APP5 is not used by this VCEP. Details ▾Hide ▴
BS2 N/AATM HBOP VCEP states BS2 should not be used because ATM has incomplete penetrance. Details ▾Hide ▴
BS4 N/AATM HBOP VCEP states BS4 should not be used. Details ▾Hide ▴
BP1 N/AATM HBOP VCEP states BP1 should not be used. Details ▾Hide ▴
BP3 N/AATM HBOP VCEP states BP3 should not be used. Details ▾Hide ▴
BP5 N/AATM HBOP VCEP states BP5 should not be used. Details ▾Hide ▴
BP6 N/ABP6 is not used by this VCEP. Details ▾Hide ▴
BP7 N/AATM BP7 applies to synonymous or deep intronic variants, not to this exonic frameshift deletion. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants or RNA evidence showing no aberrant splice defect.
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.8395_8404del
- Protein (HGVS p.)
- NP_000042.3:p.(Phe2799LysfsTer4)
- GRCh38
- chr11:108343337 ATTTCAGTGCC>A
- GRCh37
- chr11:108214064 ATTTCAGTGCC>A
Gene diagram
Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.4. Select a row to find it on the plot.
ATMNM_000051.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATM
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
Statements
No population statements were recorded.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 is not applied. The variant is not a missense change, SpliceAI does not predict splice impact (max delta 0.07), and the ATM specification notes splice-prediction PP3 should not be added on top of PVS1-based loss-of-function interpretation. Details ▾Hide ▴
Rule
Missense REVEL >.7333 or splicing SpliceAI >=0.2
Evidence considered
- SpliceAI max delta 0.07
Sources
BP4 SpliceAI shows no significant splice impact (max delta 0.07), but BP4 is not used here because the variant is an obvious frameshift loss-of-function allele and splice-only benign computational evidence does not address the primary predicted protein-damaging mechanism. Details ▾Hide ▴
Rule
Splicing: No predicted impact via splicing (SpliceAI <=0.1).
Evidence considered
- SpliceAI max delta 0.07
Sources
BP7 N/AATM BP7 applies to synonymous or deep intronic variants, not to this exonic frameshift deletion. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants or RNA evidence showing no aberrant splice defect.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/639508985
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/186242/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108214064-ATTTCAGTGCC-A?da…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108343337-ATTTCAGTGCC-A…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.8395…
- OncoKB ↗www.oncokb.org/gene/ATM/F2799Kfs*
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
ClinVar
This variant has been reported in ClinVar as Pathogenic (23 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV53730617, n = 6 times).