About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.4397_4398delinsCG, p.(Arg1466Pro)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
PS3Supporting
PS3 · supporting
In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence. Under ATM VCEP rules, functional evidence showing failure to rescue an ATM-specific feature supports PS3 at supporting strength, although assay-level confirmation for this specific entry should be completed during final review.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1, which is below the ATM VCEP PM2_supporting threshold of less than or equal to 0.001%. It is also absent from gnomAD v2.1, supporting rarity in population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 supporting, PM2 supporting; no rule matched the adjudicated criteria.
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 ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies 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: 2 met · 11 not met · 0 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.4397_4398delinsCG (p.Arg1466Pro) variant has been reported in ClinVar, where the overall expert-panel classification is uncertain significance and additional submissions range from uncertain significance to likely pathogenic and pathogenic.
This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM VCEP PM2_supporting population threshold of less than or equal to 0.001%.
In an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence, supporting an abnormal ATM protein effect.
SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.01, and the equivalent c.4397G>C missense representation has a REVEL score of 0.677 in the ATM VCEP supplementary variant table, which is below the ATM PP3 threshold of greater than 0.7333 and above the BP4 threshold of less than or equal to 0.249.
No criteria match.
Met · 2
PS3 SupportingIn an ATM VCEP supplementary variant table, the equivalent single-nucleotide representation c.4397G>C (p.Arg1466Pro) is listed as non-functional with high confidence. Under ATM VCEP rules, functional evidence showing failure to rescue an ATM-specific feature supports PS3 at supporting strength, although assay-level confirmation for this specific entry should be completed during final review. Details ▾Hide ▴
Rule
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
- Equivalent representation c.4397G>C corresponds to p.Arg1466Pro
- Supplementary table classification: Non-functional
- Confidence listed as High
Still missing
- The supplementary entry should be cross-checked against the underlying assay-level evidence before final sign-out.
- No direct variant-specific radiosensitivity rescue result was identified here to support a higher PS3 strength.
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1, which is below the ATM VCEP PM2_supporting threshold of less than or equal to 0.001%. It is also absent from gnomAD v2.1, supporting rarity in population databases. Details ▾Hide ▴
Rule
Frequency ≤.001% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- ATM PM2 threshold <=0.001%
Sources
Not met · 11 · evaluated, threshold not reached
PVS1 This variant is represented at the protein level as p.(Arg1466Pro) and does not fall within the ATM VCEP null-variant categories for PVS1. SpliceAI predicts no significant splice impact with a max delta score of 0.01, so current evidence does not support a PVS1-based loss-of-function mechanism. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Arg1466Pro)
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
- SpliceAI max delta score 0.01
Still missing
- No RNA study was identified for this exact variant.
- No evidence was identified that this change causes a truncating or canonical splice-disrupting event.
Sources
PS1 This variant results in the missense change p.(Arg1466Pro). No different nucleotide change already established as pathogenic and producing the same amino acid substitution was identified, so PS1 is not met. Details ▾Hide ▴
PS4 This variant has been reported in ClinVar, but no case-control study or exact-variant enrichment data meeting the ATM VCEP PS4 threshold of p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, were identified. PS4 is not met. Details ▾Hide ▴
PM3 No confirmed in trans observations with a pathogenic or likely pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 is not met. Details ▾Hide ▴
Evidence considered
- ATM PM3 requires point-based proband evidence
- No qualifying PM3 observations identified
Still missing
- No qualifying phase data were identified.
- No qualifying affected proband observations were identified for PM3 point assignment.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No segregation data were identified for this variant, so PP1 is not met. Details ▾Hide ▴
Evidence considered
- ATM PP1 requires affected-relative segregation data
- No qualifying segregation evidence identified
Still missing
- No family segregation report was identified.
- No informative affected-relative data were identified.
Sources
PP3 SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the ATM splice PP3 threshold of at least 0.2. In the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is below the ATM missense PP3 threshold of greater than 0.7333. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Equivalent c.4397G>C REVEL score 0.677
- ATM PP3 thresholds: SpliceAI >=0.2 or REVEL >0.7333
Still missing
- No additional computational evidence meeting the ATM PP3 threshold was identified.
Sources
BA1 This variant is absent from gnomAD v4.1 and does not meet the ATM BA1 threshold of greater than 0.5% population frequency. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v4.1 and does not meet the ATM BS1 threshold of greater than 0.05% population frequency. Details ▾Hide ▴
BS3 No well-established study showing normal ATM function or rescue of radiosensitivity for this variant was identified. Available evidence does not support benign functional evidence, so BS3 is not met. Details ▾Hide ▴
Evidence considered
- ATM BS3 requires rescue of ATM-specific function and/or radiosensitivity
- No normal-function result identified for this variant
Still missing
- No variant-specific assay showing normal ATM-specific activity was identified.
- No variant-specific assay showing rescue of radiosensitivity was identified.
Sources
BP2 No qualifying co-occurrence evidence in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual was identified, so BP2 is not met. Details ▾Hide ▴
Evidence considered
- ATM BP2 requires point-based unaffected co-occurrence evidence
- No qualifying BP2 observations identified
Still missing
- No qualifying phase data were identified.
- No qualifying unaffected co-occurrence observations were identified for BP2 point assignment.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
BP4 SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is within the ATM BP4 splice range of less than or equal to 0.1. However, in the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is above the ATM BP4 missense threshold of less than or equal to 0.249. Because the missense prediction does not support a benign effect, BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Equivalent c.4397G>C REVEL score 0.677
- ATM BP4 missense threshold <=0.249
Still missing
- No low missense predictor score meeting the ATM BP4 threshold was identified.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo evidence is not an applicable ATM VCEP criterion for this condition framework. Details ▾Hide ▴
PM1 N/APM1 is not applicable in the ATM VCEP framework because germline mutational hotspots and domains are not considered sufficiently specific for this code. Details ▾Hide ▴
PM4 N/APM4 is reserved by the ATM VCEP for stop-loss variants and does not apply to this missense variant. Details ▾Hide ▴
PM5 N/APM5 is not used for ATM missense variants in this framework. The ATM VCEP limits PM5 to truncating or qualifying splice variants upstream of p.Arg3047. Details ▾Hide ▴
PM6 N/AAssumed de novo evidence is not an applicable ATM VCEP criterion for this condition framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable for ATM because missense variation is not sufficiently constrained to support this criterion. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the ATM VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
BS2 N/ABS2 is not applicable for ATM because reduced penetrance limits interpretation of observations in healthy individuals. Details ▾Hide ▴
BS4 N/ABS4 is not applicable in the ATM VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable for ATM because pathogenic missense variants are known in this gene. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the ATM VCEP framework. Details ▾Hide ▴
BP5 N/ABP5 is not applicable in the ATM VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is reserved for synonymous and qualifying deep intronic variants and does not apply to this missense variant. Details ▾Hide ▴
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.4397_4398delinsCG
- Protein (HGVS p.)
- NP_000042.3:p.(Arg1466Pro)
- GRCh38
- chr11:108289762 GA>CG
- GRCh37
- chr11:108160489 GA>CG
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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the ATM splice PP3 threshold of at least 0.2. In the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is below the ATM missense PP3 threshold of greater than 0.7333. PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Equivalent c.4397G>C REVEL score 0.677
- ATM PP3 thresholds: SpliceAI >=0.2 or REVEL >0.7333
Still missing
- No additional computational evidence meeting the ATM PP3 threshold was identified.
Sources
BP4 SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is within the ATM BP4 splice range of less than or equal to 0.1. However, in the ATM VCEP supplementary variant table, the equivalent c.4397G>C missense representation has a REVEL score of 0.677, which is above the ATM BP4 missense threshold of less than or equal to 0.249. Because the missense prediction does not support a benign effect, BP4 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Equivalent c.4397G>C REVEL score 0.677
- ATM BP4 missense threshold <=0.249
Still missing
- No low missense predictor score meeting the ATM BP4 threshold was identified.
Sources
BP7 N/ABP7 is reserved for synonymous and qualifying deep intronic variants and does not apply to this missense variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 ↗
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/254753/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108160489-GA-CG?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108289762-GA-CG?dataset…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.4397…
- OncoKB ↗www.oncokb.org/gene/ATM/R1466P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.4397_4398delinsCG
- 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 Uncertain significance (4 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance 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 = 0.01).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.