About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.4300A>T, p.(Lys1434Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change predicted to introduce a premature stop codon at Lys1434. The ATM VCEP framework recognizes loss of function as an established disease mechanism for ATM and states that ATM exons in the reference transcript are constitutive without major rescue isoforms, supporting application of PVS1 for this truncating variant.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its population frequency is therefore below the ATM PM2_Supporting threshold of 0.001%, so PM2_Supporting is met.
PM5Supporting
PM5 · supporting
This nonsense variant introduces a premature stop at Lys1434, which is upstream of the ATM VCEP truncation cutoff at p.Arg3047Ter; under the ATM gene-specific rule, truncating variants with premature termination codons upstream of p.Arg3047Ter meet PM5_Supporting.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PM5 supporting, PM2 supporting, PVS1 very strong; maps to Pathogenic.
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.
gnomAD v2.1
Absent from gnomAD v2.1.
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 ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
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: 3 met · 4 not met · 6 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The ATM c.4300A>T (p.Lys1434Ter; p.K1434*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the ATM VCEP PM2_Supporting threshold of 0.001% and well below the BS1 (>0.05%) and BA1 (>0.5%) thresholds.
This is a nonsense variant predicted to introduce a premature stop codon at Lys1434; SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting interpretation as a truncating loss-of-function event rather than a splice-altering event.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a nonsense change predicted to introduce a premature stop codon at Lys1434. The ATM VCEP framework recognizes loss of function as an established disease mechanism for ATM and states that ATM exons in the reference transcript are constitutive without major rescue isoforms, supporting application of PVS1 for this truncating variant. Details ▾Hide ▴
Rule
Use ATM PVS1 Decision Tree.
Evidence considered
- Variant bucket: nonsense
- ATM loss of function eligible for PVS1
- ATM VCEP PVS1 decision tree applies to truncating variants
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. Its population frequency is therefore below the ATM PM2_Supporting threshold of 0.001%, so PM2_Supporting is met. Details ▾Hide ▴
Rule
Frequency ≤0.001% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 absent
- gnomAD v2.1 absent
- ATM PM2 threshold ≤0.001%
Sources
PM5 SupportingThis nonsense variant introduces a premature stop at Lys1434, which is upstream of the ATM VCEP truncation cutoff at p.Arg3047Ter; under the ATM gene-specific rule, truncating variants with premature termination codons upstream of p.Arg3047Ter meet PM5_Supporting. Details ▾Hide ▴
Rule
Apply PM5_Supporting to truncating variants with premature termination codons upstream of p.Arg3047.
Evidence considered
- ATM PM5 uses a truncation-cutoff rule rather than classic same-residue PM5.
- Variant protein consequence p.(Lys1434Ter)/p.(K1434*) is upstream of p.Arg3047Ter.
Sources
cspec ↗pm5_candidates
Not met · 4 · evaluated, threshold not reached
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the ATM PP3 splicing threshold of 0.2. A BayesDel score of 0.634849 is available, but the ATM VCEP PP3 rule is defined for missense REVEL evidence or for predicted splice-impact evidence and does not support PP3 for this truncating variant without predicted splice disruption. Details ▾Hide ▴
Rule
PP3 splicing requires SpliceAI ≥0.2; missense requires REVEL >0.7333.
Evidence considered
- SpliceAI max delta 0.03
- BayesDel 0.634849
- ATM PP3 threshold SpliceAI ≥0.2 or missense REVEL >0.7333
Sources
BA1 This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% filtering allele frequency. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 absent
- ATM BA1 threshold >0.5%
Sources
BS1 This variant is absent from gnomAD v4.1, which is below the ATM BS1 threshold of greater than 0.05% filtering allele frequency. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 absent
- ATM BS1 threshold >0.05%
Sources
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.03, which is below the ATM BP4 splicing threshold of 0.1. However, BP4 is not met because this variant introduces a premature stop codon and therefore is not predicted to have no impact on the gene product; the available BayesDel score of 0.634849 is also not used by the ATM VCEP BP4 rule for this truncating variant. Details ▾Hide ▴
Rule
BP4 splicing requires SpliceAI ≤0.1; missense requires REVEL ≤0.249.
Evidence considered
- SpliceAI max delta 0.03
- BayesDel 0.634849
- ATM BP4 threshold SpliceAI ≤0.1 or missense REVEL ≤0.249
Sources
Not assessed · 6 · no assessment recorded
PS3 No well-established functional study was identified showing that this specific variant impairs ATM-specific functional rescue, so PS3 cannot be assessed. Details ▾Hide ▴
Rule
PS3 requires ATM-specific damaging functional evidence.
Evidence considered
- No PMID-backed functional evidence identified in retrieved materials.
Still missing
- Need validated ATM functional loss data for this exact variant.
Sources
PS4 No case-control study or other evidence showing a statistically increased prevalence of this variant in affected individuals was identified, so PS4 cannot be assessed. Details ▾Hide ▴
PM3 No proband data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 point-based assignment per ATM PM3/BP2 table.
Evidence considered
- ATM PM3 requires point-based evidence from A-T probands with defined phase/zygosity.
Still missing
- Need phenotype-qualified A-T proband data with phase information or qualifying homozygous observations.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
AR condition: segregation in affected relatives.
Evidence considered
- ATM PP1 requires segregation evidence
- none identified.
Still missing
- Need family-based segregation data in an appropriate ATM disease context.
Sources
BS3 No well-established functional study was identified showing normal ATM function or rescue for this specific variant, so BS3 cannot be assessed. Details ▾Hide ▴
Rule
BS3 requires ATM functional rescue evidence.
Evidence considered
- No PMID-backed functional evidence identified in retrieved materials.
Still missing
- Need validated ATM functional rescue data for this exact variant.
Sources
BP2 No co-occurrence data were identified showing this variant in trans or in cis with another pathogenic or likely pathogenic ATM variant, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
BP2 point-based assignment per ATM PM3/BP2 table.
Evidence considered
- ATM VCEP requires point-based BP2 evidence from unaffected individuals with phase information.
Still missing
- Need validated phase and phenotype data for any co-occurring ATM variant.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this variant is a nonsense change and no same-amino-acid or qualifying splice-event comparator evidence was identified under the ATM PS1 framework. Details ▾Hide ▴
Evidence considered
- ATM PS1 is defined for missense or qualifying splice-event comparators.
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 N/APS2 is not applicable because the ATM VCEP does not use de novo evidence for ATM in this framework. Details ▾Hide ▴
PM1 N/APM1 is not applicable because the ATM VCEP does not use hotspot or critical-domain PM1 for ATM. Details ▾Hide ▴
PM4 N/APM4 is not applicable because the ATM VCEP uses PM4 only for stop-loss variants, and this variant is a nonsense change. Details ▾Hide ▴
PM6 N/APM6 is not applicable because the ATM VCEP does not use de novo evidence for ATM variant interpretation in this framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable because the ATM VCEP does not use PP2 for ATM. Details ▾Hide ▴
PP4 N/APP4 is not applicable because the ATM VCEP does not use this criterion for ATM in either the dominant cancer-predisposition or recessive A-T context. Details ▾Hide ▴
PP5 N/APP5 is not applicable because this criterion is not used by the ATM VCEP. Details ▾Hide ▴
BS2 N/ABS2 is not applicable because the ATM VCEP does not use BS2 for ATM due to incomplete penetrance. Details ▾Hide ▴
BS4 N/ABS4 is not applicable because the ATM VCEP does not use lack of segregation evidence for ATM in this framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable because the ATM VCEP does not use BP1 for ATM. Details ▾Hide ▴
BP3 N/ABP3 is not applicable because the ATM VCEP does not use this criterion for ATM variants. Details ▾Hide ▴
BP5 N/ABP5 is not applicable because the ATM VCEP does not use this criterion for ATM. Details ▾Hide ▴
BP6 N/ABP6 is not applicable because this criterion is not used by the ATM VCEP. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this variant is not synonymous and not a deep intronic variant. Details ▾Hide ▴
Evidence considered
- ATM BP7 is restricted to synonymous or deep intronic variants
- or RNA evidence for lack of splice defect in those classes.
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.4300A>T
- Protein (HGVS p.)
- NP_000042.3:p.(Lys1434Ter)
- GRCh38
- chr11:108289665 A>T
- GRCh37
- chr11:108160392 A>T
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 |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the ATM PP3 splicing threshold of 0.2. A BayesDel score of 0.634849 is available, but the ATM VCEP PP3 rule is defined for missense REVEL evidence or for predicted splice-impact evidence and does not support PP3 for this truncating variant without predicted splice disruption. Details ▾Hide ▴
Rule
PP3 splicing requires SpliceAI ≥0.2; missense requires REVEL >0.7333.
Evidence considered
- SpliceAI max delta 0.03
- BayesDel 0.634849
- ATM PP3 threshold SpliceAI ≥0.2 or missense REVEL >0.7333
Sources
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.03, which is below the ATM BP4 splicing threshold of 0.1. However, BP4 is not met because this variant introduces a premature stop codon and therefore is not predicted to have no impact on the gene product; the available BayesDel score of 0.634849 is also not used by the ATM VCEP BP4 rule for this truncating variant. Details ▾Hide ▴
Rule
BP4 splicing requires SpliceAI ≤0.1; missense requires REVEL ≤0.249.
Evidence considered
- SpliceAI max delta 0.03
- BayesDel 0.634849
- ATM BP4 threshold SpliceAI ≤0.1 or missense REVEL ≤0.249
Sources
BP7 N/ABP7 is not applicable because this variant is not synonymous and not a deep intronic variant. Details ▾Hide ▴
Evidence considered
- ATM BP7 is restricted to synonymous or deep intronic variants
- or RNA evidence for lack of splice defect in those classes.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.634849.
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
Open source ↗
Cancer hotspots
Captured Cancer Hotspots 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/?term=NM_000051.4%3Ac.4300A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108160392-A-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108289665-A-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.4300…
- OncoKB ↗www.oncokb.org/gene/ATM/K1434*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.4300A%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.634849.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.