About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.4158dup, p.(Lys1387Ter)
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: 4
Benign evidence criteria: 1
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
This variant creates a premature termination at Lys1387 in the ATM reference transcript NM_000051.3, a transcript for which the ATM HBOP VCEP considers all exons constitutive. The stop occurs in exon 28 with 13 downstream exons remaining, and SpliceAI does not suggest an alternative splice-mediated rescue mechanism (max delta score 0.02), so full-strength PVS1 is supported under the ATM VCEP PVS1 framework.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4.
PM5Supporting
PM5 · supporting
This truncating variant introduces a premature stop at Lys1387, which is upstream of the ATM HBOP VCEP truncation cutoff at p.Arg3047Ter, so the ATM gene-specific PM5_Supporting rule is met.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM BP4 splice threshold of 0.1. This supports the expected truncating interpretation rather than an alternative splice-mediated effect.
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, BP4 supporting, PP5 supporting; 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.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 5 met · 3 not met · 6 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
The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.
This variant is absent from gnomAD v4.1 and gnomAD v2.1, which supports PM2_Supporting and does not meet the BA1 or BS1 population thresholds.
This variant introduces a premature stop at Lys1387 in ATM, and the ATM HBOP VCEP framework supports full-strength PVS1 for this truncating event; the same gene-specific framework also supports PM5_Supporting because the stop is upstream of the ATM truncation cutoff at p.Arg3047Ter.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which supports BP4 and does not support PP3 under the ATM VCEP splice thresholds.
No criteria match.
Met · 5
PVS1 Very strongThis variant creates a premature termination at Lys1387 in the ATM reference transcript NM_000051.3, a transcript for which the ATM HBOP VCEP considers all exons constitutive. The stop occurs in exon 28 with 13 downstream exons remaining, and SpliceAI does not suggest an alternative splice-mediated rescue mechanism (max delta score 0.02), so full-strength PVS1 is supported under the ATM VCEP PVS1 framework. Details ▾Hide ▴
Rule
ATM PVS1 Decision Tree
Evidence considered
- Protein consequence p.(Lys1387Ter)
- ATM loss of function is an established disease mechanism in this VCEP framework
- Variant lies in exon 28 with multiple downstream exons
- SpliceAI max delta 0.02
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4. Details ▾Hide ▴
Rule
PM2_Supporting for frequency ≤0.001% in gnomAD v4
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- ATM PM2_Supporting threshold ≤0.001%
Sources
PM5 SupportingThis truncating variant introduces a premature stop at Lys1387, which is upstream of the ATM HBOP VCEP truncation cutoff at p.Arg3047Ter, so the ATM gene-specific PM5_Supporting rule is met. Details ▾Hide ▴
Rule
Apply as PM5_Supporting to truncating variants with premature termination codons upstream of p.Arg3047
Evidence considered
- Protein consequence p.(Lys1387Ter)
- ATM PM5 uses truncation-cutoff logic rather than classic same-residue missense logic
- Lys1387Ter is upstream of Arg3047Ter
Sources
cspec ↗pm5_candidates
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
BP4 SupportingSpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM BP4 splice threshold of 0.1. This supports the expected truncating interpretation rather than an alternative splice-mediated effect. Details ▾Hide ▴
Rule
Splicing BP4 requires SpliceAI ≤0.1; missense BP4 requires REVEL ≤0.249
Evidence considered
- SpliceAI max delta 0.02
- ATM BP4 splice threshold ≤0.1
Sources
Not met · 3 · evaluated, threshold not reached
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM PP3 splice threshold of 0.2. REVEL and BayesDel are not applicable here because this is not a missense SNV. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥0.2; missense PP3 requires REVEL >0.7333
Evidence considered
- SpliceAI max delta 0.02
- ATM PP3 splice threshold ≥0.2
- REVEL unavailable because variant is not a missense SNV
Sources
BA1 This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% group maximum filtering allele frequency. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 absent
- 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% group maximum filtering allele frequency. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset
Evidence considered
- gnomAD v4.1 absent
- BS1 threshold >0.05%
Sources
Not assessed · 6 · no assessment recorded
PS3 No reviewed variant-specific assay showed failure to rescue ATM-specific function or radiosensitivity for this variant under the ATM VCEP functional framework, so PS3 was not assigned. Details ▾Hide ▴
Rule
PS3 requires failure to rescue ATM-specific function and/or radiosensitivity per VCEP framework
Evidence considered
- ATM functional guidance reviewed
- Curated literature leads identified
- but no exact PS3-grade result for this variant was extracted
Still missing
- Variant-specific validated functional evidence meeting ATM PS3 assay requirements
Sources
PS4 The available evidence confirms ClinVar reporting, but no reviewed case-control dataset provided a p-value of 0.05 or less together with an odds ratio, hazard ratio, or relative risk meeting the ATM PS4 threshold, so PS4 was not assigned. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5
Evidence considered
- ClinVar pathogenic expert panel assertion
- No qualifying ATM PS4 case-control statistics identified in reviewed files
Still missing
- Variant-specific case-control data
- Non-duplicated unrelated affected case counts with an appropriate control comparison
Sources
PM3 No reviewed patient-level evidence established this variant in trans with another pathogenic or likely pathogenic ATM variant with sufficient phenotype and phase detail to assign PM3 under the ATM point-based framework. Details ▾Hide ▴
Rule
PM3 strength is assigned from summed proband points
Evidence considered
- ATM PM3/BP2 point-based framework reviewed
- ClinVar-linked publications identified but no extractable PM3 point assignment from reviewed files
Still missing
- Unrelated affected probands with confirmed trans phase
- Phenotype classification within the ATM PM3 framework
- Point total from documented probands
Sources
PP1 No reviewed segregation data documented this variant tracking with disease in affected relatives in a way that meets the ATM AR-specific PP1 framework, so PP1 was not assigned. Details ▾Hide ▴
Rule
AR PP1 requires segregation in affected relatives
Evidence considered
- ClinVar-linked literature reviewed for segregation leads
- No extractable PP1-grade segregation evidence identified in reviewed files
Still missing
- Family segregation data with both ATM variants identified in the proband
- Affected relative counts meeting PP1 thresholds
Sources
BS3 No reviewed variant-specific assay showed rescue of ATM-specific function or radiosensitivity for this variant, so BS3 was not assigned. Details ▾Hide ▴
Rule
BS3 requires rescue of ATM-specific function and/or radiosensitivity per VCEP framework
Evidence considered
- ATM functional guidance reviewed
- Curated literature leads identified
- but no exact BS3-grade rescue result for this variant was extracted
Still missing
- Variant-specific validated benign functional rescue data meeting ATM VCEP assay requirements
Sources
BP2 No reviewed evidence showed this variant in cis or in an unaffected adult in trans or homozygous with another pathogenic or likely pathogenic ATM variant, so BP2 cannot be assigned from the available data. Details ▾Hide ▴
Rule
BP2 requires point-based evidence from unaffected co-occurrence scenarios
Evidence considered
- ATM PM3/BP2 point-based framework reviewed
- ClinVar-linked publications identified but no usable BP2-grade co-occurrence detail extracted
Still missing
- Patient-level co-occurrence data with phase
- Adult unaffected status for any potential BP2 observation
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AATM HBOP VCEP guidance limits PS1 use to missense changes and defined splicing scenarios, whereas this variant is truncating. Details ▾Hide ▴
Rule
ATM PS1 is for missense or specified splice-comparator scenarios
Evidence considered
- Variant consequence p.(Lys1387Ter)
- ATM PS1 guidance reviewed
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 VCEPATM HBOP VCEP guidance states PS2 should not be used for ATM. Details ▾Hide ▴
PM1 VCEPATM HBOP VCEP guidance states PM1 should not be used for ATM because germline mutational hotspots are not well defined. Details ▾Hide ▴
PM4 N/AATM HBOP VCEP guidance limits PM4 to stop-loss variants, and this variant is truncating rather than stop-loss. Details ▾Hide ▴
Rule
Use for stop-loss variants only
Evidence considered
- Variant consequence p.(Lys1387Ter)
Sources
PM6 VCEPATM HBOP VCEP guidance states PM6 should not be used for ATM. Details ▾Hide ▴
PP2 VCEPATM HBOP VCEP guidance states PP2 should not be used for ATM. Details ▾Hide ▴
PP4 VCEPATM HBOP VCEP guidance states PP4 should not be used for ATM. Details ▾Hide ▴
BS2 VCEPATM HBOP VCEP guidance states BS2 should not be used for ATM because of incomplete penetrance. Details ▾Hide ▴
BS4 VCEPATM HBOP VCEP guidance states BS4 should not be used for ATM. Details ▾Hide ▴
BP1 VCEPATM HBOP VCEP guidance states BP1 should not be used for ATM. Details ▾Hide ▴
BP3 VCEPATM HBOP VCEP guidance states BP3 is not applicable for ATM. Details ▾Hide ▴
BP5 VCEPATM HBOP VCEP guidance states BP5 should not be used for ATM. Details ▾Hide ▴
BP6 VCEPATM HBOP VCEP guidance states BP6 is not for use. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or deep intronic variants, whereas this variant is truncating. Details ▾Hide ▴
Rule
BP7 applies to synonymous and deep intronic variants
Evidence considered
- Variant is truncating
- not synonymous or deep intronic
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.4158dup
- Protein (HGVS p.)
- NP_000042.3:p.(Lys1387Ter)
- GRCh38
- chr11:108289023 A>AT
- GRCh37
- chr11:108159750 A>AT
- ClinVar
- 3148196
Gene diagram
Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.3. Select a row to find it on the plot.
ATMNM_000051.3
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM BP4 splice threshold of 0.1. This supports the expected truncating interpretation rather than an alternative splice-mediated effect. Details ▾Hide ▴
Rule
Splicing BP4 requires SpliceAI ≤0.1; missense BP4 requires REVEL ≤0.249
Evidence considered
- SpliceAI max delta 0.02
- ATM BP4 splice threshold ≤0.1
Sources
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM PP3 splice threshold of 0.2. REVEL and BayesDel are not applicable here because this is not a missense SNV. Details ▾Hide ▴
Rule
Splicing PP3 requires SpliceAI ≥0.2; missense PP3 requires REVEL >0.7333
Evidence considered
- SpliceAI max delta 0.02
- ATM PP3 splice threshold ≥0.2
- REVEL unavailable because variant is not a missense SNV
Sources
BP7 N/ABP7 is intended for synonymous or deep intronic variants, whereas this variant is truncating. Details ▾Hide ▴
Rule
BP7 applies to synonymous and deep intronic variants
Evidence considered
- Variant is truncating
- not synonymous or deep intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 27413114 ↗ATM Mutations in Cancer: Therapeutic Implications.No paper-specific finding is recorded.
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PMID 30348496 ↗Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.No paper-specific finding is recorded.
-
PMID 30553448 ↗Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.No paper-specific finding is recorded.
-
PMID 23807571 ↗Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.Huang Y et al. · 2013No paper-specific finding is recorded.
-
PMID 25614872 ↗Ten new ATM alterations in Polish patients with ataxia-telangiectasia.Podralska MJ et al. · 2014No paper-specific finding is recorded.
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PMID 26896183 ↗Longitudinal analysis of the neurological features of ataxia-telangiectasia.Jackson TJ et al. · 2016No paper-specific finding is recorded.
-
PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.No paper-specific finding is recorded.
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
Recorded maximum delta 0.020
Open source ↗
ClinVar
3 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
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/3148196/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108159750-A-AT?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108289023-A-AT?dataset=…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.4158…
- OncoKB ↗www.oncokb.org/gene/ATM/K1387*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.4158dup
- 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 has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3148196)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.