About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.419A>T, p.(Asp140Val)
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
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. A frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%, so PM2_Supporting is met.
PP3Supporting
PP3 · supporting
This missense variant has a REVEL score of 0.815, which is above the ATM PP3 threshold of greater than 0.7333. SpliceAI shows a maximum delta score of 0.06, which does not suggest a splice effect, so the computational evidence supports a damaging missense effect and PP3 is met at supporting strength.
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: PM2 supporting, PP3 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.
SpliceAI score
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
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: 2 met · 3 not met · 7 not assessed · 16 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.419A>T (p.(Asp140Val), p.(D140V)) 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, and its frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%.
In an ATM supplementary functional dataset, p.(D140V) was classified as Functional with High confidence, but the available retrieved evidence does not provide the assay-level rescue details required to assign ATM PS3 or BS3 in this pass.
Computational evidence supports a damaging missense effect: REVEL is 0.815, above the ATM PP3 threshold of greater than 0.7333, BayesDel is 0.278827, and SpliceAI shows no significant splice impact with a maximum delta score of 0.06.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. A frequency of 0 is below the ATM PM2_Supporting threshold of less than or equal to 0.001%, so PM2_Supporting is met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 absent
- gnomAD v2.1 absent
- ATM PM2 threshold <=0.001%
Sources
PP3 SupportingThis missense variant has a REVEL score of 0.815, which is above the ATM PP3 threshold of greater than 0.7333. SpliceAI shows a maximum delta score of 0.06, which does not suggest a splice effect, so the computational evidence supports a damaging missense effect and PP3 is met at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL 0.815
- SpliceAI max delta 0.06
- BayesDel 0.278827
Sources
Not met · 3 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BA1 threshold of greater than 0.5%. BA1 is not met. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v4.1, so its frequency is not above the ATM BS1 threshold of greater than 0.05%. BS1 is not met. Details ▾Hide ▴
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, the REVEL score is 0.815, which is well above the ATM BP4 missense threshold of less than or equal to 0.249. Available computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.815
- SpliceAI max delta 0.06
- ATM BP4 missense threshold <=0.249
Sources
Not assessed · 7 · no assessment recorded
PS1 No pathogenic or likely pathogenic comparator causing the same amino acid change or the same defined splice event was identified from the available ATM-specific materials, so PS1 was not established. Details ▾Hide ▴
Evidence considered
- ATM PS1 requires a qualified pathogenic comparator and comparable splicing context
Still missing
- A confirmed ATM VCEP-qualified same-amino-acid or same-splice-event pathogenic comparator would be needed.
Sources
cspec ↗vcep_atm_ps1_1_5
PS3 An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not provide assay-level rescue results for ATM-specific function and radiosensitivity needed to apply ATM PS3. Details ▾Hide ▴
Evidence considered
- Supplementary Table S1 row for c.419A>T / p.(D140V): Classification Functional
- Confidence High
- ATM PS3 requires failure to rescue ATM-specific function and/or radiosensitivity
Still missing
- Direct review of the underlying functional assay data would be needed to determine whether ATM PS3 criteria are satisfied.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
PS4 No case-control data or enrichment data meeting the ATM PS4 rule were identified. This variant is also absent from ClinVar, so there is no assembled case series evidence to support PS4 in this pass. Details ▾Hide ▴
PM3 No proband data showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 points cannot be assigned. Details ▾Hide ▴
Evidence considered
- No reported recessive case data in reviewed materials
Still missing
- Phase-confirmed or phase-unknown recessive proband data would be needed for ATM PM3 scoring.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No family segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
Evidence considered
- No segregation evidence in reviewed materials
Still missing
- Documented segregation data in affected relatives would be needed.
Sources
BS3 An ATM supplementary functional dataset lists p.(D140V) as Functional with High confidence, but the available retrieved evidence in this pass does not show the specific rescue results for ATM-specific activity and radiosensitivity required to assign ATM BS3. Details ▾Hide ▴
Evidence considered
- Supplementary Table S1 row for c.419A>T / p.(D140V): Classification Functional
- Confidence High
- ATM BS3 requires rescue evidence for ATM-specific feature and/or radiosensitivity
Still missing
- Direct review of the underlying functional assay evidence would be needed to determine whether BS3_Supporting or BS3_Moderate can be applied.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP2 No co-occurrence data in trans with a pathogenic ATM variant in unaffected individuals were identified, so BP2 points cannot be assigned. Details ▾Hide ▴
Evidence considered
- No qualifying co-occurrence evidence in reviewed materials
Still missing
- Documented co-occurrence data meeting the ATM BP2 point framework would be needed.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-level loss-of-function variant. ATM loss of function is an established disease mechanism, but this variant does not meet the ATM PVS1 decision-tree entry criteria. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Asp140Val)/p.(D140V)
- Generic PVS1 scaffold states variant is outside default null-variant buckets
- ATM VCEP includes gene-specific PVS1 guidance
Sources
PS2 VCEPThe ATM VCEP framework marks PS2 as not applicable for this gene-specific specification. Details ▾Hide ▴
PM1 VCEPThe ATM VCEP framework marks PM1 as not applicable. Details ▾Hide ▴
PM4 N/AATM PM4 is specified for stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Asp140Val)
- ATM PM4 rule applies to stop-loss variants
Sources
PM5 N/AIn the ATM VCEP framework, PM5 is a truncation-cutoff or related non-missense rule rather than classic same-residue missense PM5. This missense variant is therefore not eligible for PM5 under the governing rule set. Details ▾Hide ▴
Evidence considered
- pm5_candidates marked pm5_mode as truncation_cutoff_gene_specific
- eligible_for_classic_pm5_search=false
Sources
cspec ↗pm5_candidates
PM6 VCEPThe ATM VCEP framework marks PM6 as not applicable. Details ▾Hide ▴
PP2 VCEPThe ATM VCEP framework marks PP2 as not applicable. Details ▾Hide ▴
PP4 VCEPThe ATM VCEP framework marks PP4 as not applicable. Details ▾Hide ▴
PP5 VCEPThe ATM VCEP framework marks PP5 as not applicable. Details ▾Hide ▴
BS2 VCEPThe ATM VCEP framework marks BS2 as not applicable. Details ▾Hide ▴
BS4 VCEPThe ATM VCEP framework marks BS4 as not applicable. Details ▾Hide ▴
BP1 VCEPThe ATM VCEP framework marks BP1 as not applicable. Details ▾Hide ▴
BP3 VCEPThe ATM VCEP framework marks BP3 as not applicable. Details ▾Hide ▴
BP5 VCEPThe ATM VCEP framework marks BP5 as not applicable. Details ▾Hide ▴
BP6 VCEPThe ATM VCEP framework marks BP6 as not applicable. Details ▾Hide ▴
BP7 N/AATM BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect, and this variant is a missense substitution. Details ▾Hide ▴
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.419A>T
- Protein (HGVS p.)
- NP_000042.3:p.(Asp140Val)
- GRCh38
- chr11:108235757 A>T
- GRCh37
- chr11:108106484 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.815
- BayesDel
- 0.279
How the predictions were used
PP3 SupportingThis missense variant has a REVEL score of 0.815, which is above the ATM PP3 threshold of greater than 0.7333. SpliceAI shows a maximum delta score of 0.06, which does not suggest a splice effect, so the computational evidence supports a damaging missense effect and PP3 is met at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL 0.815
- SpliceAI max delta 0.06
- BayesDel 0.278827
Sources
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, the REVEL score is 0.815, which is well above the ATM BP4 missense threshold of less than or equal to 0.249. Available computational evidence does not support BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.815
- SpliceAI max delta 0.06
- ATM BP4 missense threshold <=0.249
Sources
BP7 N/AATM BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect, and this variant is a missense substitution. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.815. BayesDel score = 0.278827.
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
Recorded maximum delta 0.060
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/?term=NM_000051.4%3Ac.419A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108106484-A-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108235757-A-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.419A…
- OncoKB ↗www.oncokb.org/gene/ATM/D140V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.419A%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 = 0.06). REVEL score = 0.815. BayesDel score = 0.278827.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
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.