About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.2207C>T, p.(Ala736Val)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
The variant is present at extremely low frequency in gnomAD v4.1 (3/1,458,952 alleles; AF 2.05627e-06; no homozygotes), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
In silico evidence supports a benign interpretation: the REVEL score is 0.103, which is at or below the ATM VCEP BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a max delta score of 0.02, below the BP4 splicing threshold of ≤0.1.
Recorded classification: Not classified
ATM CSPEC/VCEP explicit final-classification framework (criteria-combination rules from final_classification_framework.json; source cspec_ruleset v1.5.0 based on Richards et al. 2015 combining rules).
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
3 / 1,458,952 alleles
gnomAD v4.1: 3 / 1,458,952 alleles. Recorded AF 2.05627e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96223e-06; MAF= 0.00080%, 2/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76013e-05; MAF= 0.00176%, 2/113628 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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
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
Cancer Hotspots ↗
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.2207C>T (p.Ala736Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance by 4 clinical laboratories.
The variant is present at very low frequency in gnomAD, including 3 of 1458952 alleles in v4.1 with no homozygotes, which supports PM2_Supporting and is well below the ATM BS1 and BA1 frequency thresholds.
In silico evidence argues against a deleterious effect: REVEL is 0.103 and SpliceAI shows a maximum delta score of 0.02, supporting BP4 and arguing against PP3.
No criteria match.
Met · 2
PM2 SupportingThe variant is present at extremely low frequency in gnomAD v4.1 (3/1,458,952 alleles; AF 2.05627e-06; no homozygotes), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%. Details ▾Hide ▴
Rule
Frequency ≤0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, that is sufficiently rare and PM2_supporting would apply.
Evidence considered
- gnomAD v4.1 total AF 2.05627e-06; 3/1458952 alleles; homozygotes 0.
- gnomAD v2.1 total AF 7.96223e-06; 2/251186 alleles; homozygotes 0.
Sources
BP4 SupportingIn silico evidence supports a benign interpretation: the REVEL score is 0.103, which is at or below the ATM VCEP BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a max delta score of 0.02, below the BP4 splicing threshold of ≤0.1. Details ▾Hide ▴
Rule
Missense: REVEL score ≤0.249; Splicing: no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
- REVEL score 0.103.
- SpliceAI DS_AG 0.0, DS_AL 0.02, DS_DG 0.0, DS_DL 0.01; max delta score 0.02.
Sources
Not met · 3 · evaluated, threshold not reached
PP3 The missense REVEL score is 0.103, which is well below the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact (max delta score 0.02), so PP3 is not met. Details ▾Hide ▴
Rule
Missense: REVEL >0.7333; Splicing: SpliceAI ≥0.2 for qualifying variant classes.
Evidence considered
- REVEL score 0.103.
- SpliceAI max delta score 0.02.
Sources
BA1 The highest observed gnomAD v4.1 filtering allele frequency is far below the ATM VCEP BA1 threshold of >0.5%, so BA1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 grpmax FAF 7.2e-07.
- gnomAD v4.1 highest observed population AF 2.70245e-06 in European non-Finnish.
Sources
BS1 The gnomAD v4.1 frequency is far below the ATM VCEP BS1 threshold of >0.05%, so BS1 is not met. Details ▾Hide ▴
Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 highest observed population AF 2.70245e-06 in European non-Finnish.
- gnomAD v4.1 grpmax FAF 7.2e-07.
Sources
Not assessed · 7 · no assessment recorded
PS1 No established pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified from the available sources, so PS1 was not applied. Details ▾Hide ▴
Rule
Use for missense changes as long as splicing is ruled-out for both alterations.
Evidence considered
- Variant is a missense substitution p.(Ala736Val).
- SpliceAI predicts no significant splice impact (max delta score 0.02).
- No qualifying PS1 reference variant was identified in the reviewed sources.
Still missing
- A curated search for pathogenic/likely pathogenic ATM variants causing the same amino acid substitution or matching splice event would be needed to assess PS1.
Sources
PS3 No ATM-specific functional assay evidence showing failure to rescue an ATM-specific feature or radiosensitivity was identified for this variant, so PS3 was not applied. Details ▾Hide ▴
Rule
Use when a variant fails to rescue both an ATM specific feature and radiosensitivity (Moderate), or fails to rescue an ATM specific feature only (Supporting).
Evidence considered
- ATM VCEP requires variant-specific failure-to-rescue functional evidence for PS3.
- No qualifying functional result for p.(Ala736Val) was identified in the reviewed sources.
Still missing
- Published ATM functional assay data specific to p.(Ala736Val) would be needed to assess PS3.
Sources
PS4 No case-control evidence meeting the ATM VCEP PS4 threshold was identified, and the available ClinVar observation does not establish statistical enrichment in affected individuals. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.
Evidence considered
- ClinVar reports a single-submitter VUS aggregate summary.
- No qualifying ATM case-control study for this variant was identified.
Still missing
- Case-control data with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5 would be needed to assess PS4.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in affected individuals under the ATM PM3/BP2 point system, so PM3 was not applied. Details ▾Hide ▴
Rule
PM3_Supporting = 1 point; PM3 = 2 points; PM3_Strong = 4 points; PM3_VeryStrong ≥8 points.
Evidence considered
- ATM VCEP requires point-based evidence from recessive probands for PM3.
- No qualifying in-trans proband data for p.(Ala736Val) was identified.
Still missing
- Phase-aware recessive case data would be needed to assign PM3 points.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
AR condition: segregation in 1 affected relative (Supporting), 2 affected relatives (Moderate), or ≥3 affected relatives (Strong).
Evidence considered
- ATM VCEP requires segregation in affected relatives for PP1.
- No qualifying segregation evidence for p.(Ala736Val) was identified.
Still missing
- Segregation data in affected relatives would be needed to assess PP1 under the ATM recessive framework.
Sources
cspec ↗literature_pass
BS3 No ATM-specific functional assay evidence showing rescue of an ATM-specific feature or radiosensitivity was identified for this variant, so BS3 was not applied. Details ▾Hide ▴
Rule
Use when a variant rescues both an ATM specific feature and radiosensitivity (Moderate), or rescues either one (Supporting).
Evidence considered
- ATM VCEP requires variant-specific rescue data for BS3.
- No qualifying rescue assay for p.(Ala736Val) was identified.
Still missing
- Published ATM functional rescue data specific to p.(Ala736Val) would be needed to assess BS3.
Sources
BP2 No evidence was identified that this variant co-occurred in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual under the ATM PM3/BP2 point system, so BP2 was not applied. Details ▾Hide ▴
Rule
BP2 = -1 point; BP2_Moderate = -2 points; BP2_Strong ≤ -4 points.
Evidence considered
- ATM VCEP requires point-based co-occurrence evidence for BP2.
- No qualifying BP2 point evidence for p.(Ala736Val) was identified.
Still missing
- Phase-aware co-occurrence data in unaffected individuals would be needed to assign BP2 points.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AATM PVS1 is for predicted loss-of-function variants using the ATM PVS1 decision tree. NM_000051.4:c.2207C>T is a missense variant, p.(Ala736Val), so PVS1 does not apply. Details ▾Hide ▴
Rule
Use ATM PVS1 Decision Tree.
Evidence considered
- Variant normalizes to NP_000042.3:p.(Ala736Val).
- ATM VCEP specifies PVS1 for null/splice loss-of-function contexts.
Sources
cspec ↗prefetch
PS2 N/AATM VCEP marks PS2 as not applicable in this framework. Details ▾Hide ▴
PM1 N/AATM VCEP marks PM1 as not applicable in this framework. Details ▾Hide ▴
PM4 N/AATM VCEP PM4 is specified for stop-loss variants. This variant is missense, p.(Ala736Val), so PM4 does not apply. Details ▾Hide ▴
Rule
Use for stop-loss variants.
Evidence considered
- Variant normalizes to missense p.(Ala736Val).
- ATM VCEP PM4 rule is limited to stop-loss variants.
Sources
cspec ↗prefetch
PM5 N/AATM VCEP PM5 is specified for truncating or qualifying splice variants upstream of p.Arg3047. This variant is missense, so PM5 does not apply. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or qualifying NMD-prone splice variants.
Evidence considered
- Variant normalizes to missense p.(Ala736Val).
- ATM VCEP PM5 specification is limited to truncating/NMD-prone splice contexts.
Sources
cspec ↗prefetch
PM6 N/AATM VCEP marks PM6 as not applicable in this framework. Details ▾Hide ▴
PP2 N/AATM VCEP marks PP2 as not applicable in this framework. Details ▾Hide ▴
PP4 N/AATM VCEP marks PP4 as not applicable in this framework. Details ▾Hide ▴
PP5 N/AATM VCEP marks PP5 as not applicable in this framework. Details ▾Hide ▴
BS2 N/AATM VCEP marks BS2 as not applicable in this framework. Details ▾Hide ▴
BS4 N/AATM VCEP marks BS4 as not applicable in this framework. Details ▾Hide ▴
BP1 N/AATM VCEP marks BP1 as not applicable in this framework. Details ▾Hide ▴
BP3 N/AATM VCEP marks BP3 as not applicable in this framework. Details ▾Hide ▴
BP5 N/AATM VCEP marks BP5 as not applicable in this framework. Details ▾Hide ▴
BP6 N/AATM VCEP marks BP6 as not applicable in this framework. Details ▾Hide ▴
BP7 N/AATM VCEP BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or observed lack of aberrant RNA defect for silent substitutions and intronic variants.
Evidence considered
- Variant normalizes to missense p.(Ala736Val).
- ATM VCEP BP7 is directed to synonymous/deep intronic or RNA-no-defect contexts.
Sources
cspec ↗prefetch
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.2207C>T
- Protein (HGVS p.)
- NP_000042.3:p.(Ala736Val)
- GRCh38
- chr11:108256297 C>T
- GRCh37
- chr11:108127024 C>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
3 / 1,458,952 alleles
AF 2.06e-06 · 0 homozygotes · FAF 7.2e-07
gnomAD v2.1
2 / 251,186 alleles
AF 7.96e-06 · 0 homozygotes · FAF 2.92e-06
By genetic ancestry
gnomAD v4.1
AF 2.1e-06 · 3 / 1,458,952 alleles · 0 hom · FAF 7.2e-07
| European (non-Finnish)3 / 1,110,104 | 2.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 251,186 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)2 / 113,628 | 1.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.05627e-06; MAF= 0.00021%, 3/1458952 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.70245e-06; MAF= 0.00027%, 3/1110104 alleles, homozygotes = 0); grpmax FAF= 7.2e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96223e-06; MAF= 0.00080%, 2/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76013e-05; MAF= 0.00176%, 2/113628 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingIn silico evidence supports a benign interpretation: the REVEL score is 0.103, which is at or below the ATM VCEP BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a max delta score of 0.02, below the BP4 splicing threshold of ≤0.1. Details ▾Hide ▴
Rule
Missense: REVEL score ≤0.249; Splicing: no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
- REVEL score 0.103.
- SpliceAI DS_AG 0.0, DS_AL 0.02, DS_DG 0.0, DS_DL 0.01; max delta score 0.02.
Sources
PP3 The missense REVEL score is 0.103, which is well below the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact (max delta score 0.02), so PP3 is not met. Details ▾Hide ▴
Rule
Missense: REVEL >0.7333; Splicing: SpliceAI ≥0.2 for qualifying variant classes.
Evidence considered
- REVEL score 0.103.
- SpliceAI max delta score 0.02.
Sources
BP7 N/AATM VCEP BP7 is specified for synonymous and deep intronic variants or RNA evidence showing no splice defect. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, or observed lack of aberrant RNA defect for silent substitutions and intronic variants.
Evidence considered
- Variant normalizes to missense p.(Ala736Val).
- ATM VCEP BP7 is directed to synonymous/deep intronic or RNA-no-defect contexts.
Sources
cspec ↗prefetch
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
3 / 1,458,952 recorded alleles
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
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/135743/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108127024-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108256297-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.2207…
- OncoKB ↗www.oncokb.org/gene/ATM/A736V
- 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
This variant is present in gnomAD v4.1 (AF= 2.05627e-06; MAF= 0.00021%, 3/1458952 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.70245e-06; MAF= 0.00027%, 3/1110104 alleles, homozygotes = 0); grpmax FAF= 7.2e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.96223e-06; MAF= 0.00080%, 2/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76013e-05; MAF= 0.00176%, 2/113628 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.