About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.8362C>T, p.(His2788Tyr)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of <=0.001%.
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 and 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 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
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: 1 met · 6 not met · 5 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.8362C>T (p.His2788Tyr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 2 clinical laboratories.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, and the observed population frequency is therefore below the ATM PM2_Supporting threshold of <=0.001%.
A multiplex functional study classified p.His2788Tyr as non-functional with high confidence, but the available data are based on olaparib fitness assays and do not yet establish the ATM-specific rescue framework required to apply ATM PS3 or BS3 without manual review.
REVEL is 0.669, which is below the ATM PP3 threshold of >0.7333 and above the ATM BP4 missense threshold of <=0.249, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of <=0.001%. Details ▾Hide ▴
Rule
Frequency <=0.001% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- ATM PM2 applies at Supporting strength for frequency <=0.001% in gnomAD v4
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified, so PS1 is not supported. Details ▾Hide ▴
PS4 No case-control study or enrichment data showing a statistically significant excess of this variant in affected individuals were identified, so PS4 is not met. Details ▾Hide ▴
Rule
Case-control studies; p-value <=0.05 AND effect size >=2 or lower 95% CI >=1.5.
Evidence considered
- ClinVar contains only uncertain significance submissions
- No case-control odds ratio, hazard ratio, relative risk, or p-value meeting ATM PS4 thresholds was identified
Sources
PP3 REVEL is 0.669, which is below the ATM PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the splicing threshold of >=0.2. These findings do not support PP3. Details ▾Hide ▴
Rule
Missense: REVEL >.7333; Splicing: SpliceAI >=0.2.
Evidence considered
- REVEL score 0.669
- SpliceAI max delta score 0.01
Sources
BA1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BA1 threshold of >0.5%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.5% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the ATM BS1 threshold of >0.05%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.05% in gnomAD v4 dataset
Evidence considered
- Absent from gnomAD v4.1
Sources
BP4 REVEL is 0.669, which is above the ATM BP4 missense threshold of <=0.249, so benign missense prediction is not supported. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1, but this does not overcome the missense prediction result. Details ▾Hide ▴
Rule
Missense: REVEL <=.249; Splicing: SpliceAI <=0.1.
Evidence considered
- REVEL score 0.669
- SpliceAI max delta score 0.01
Sources
Not assessed · 5 · no assessment recorded
PS3 A multiplex functional study classified p.(His2788Tyr) as non-functional with high confidence, but the available assay measures olaparib-related cell fitness and does not clearly demonstrate failure to rescue both an ATM-specific feature and radiosensitivity as required for ATM PS3. Details ▾Hide ▴
Rule
Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity, or only an ATM specific feature for Supporting.
Evidence considered
- Lee et al. 2025 Table S1 lists c.8362C>T p.H2788Y as Non-functional with High confidence
- ATM CSPEC applies PS3_Moderate when a variant fails to rescue both an ATM-specific feature and radiosensitivity, and PS3_Supporting when only an ATM-specific feature is not rescued
Still missing
- An ATM VCEP-compatible functional interpretation linking this variant to failure of the required rescue framework was not identified.
Sources
PM3 No 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 framework for ATM recessive observations
Evidence considered
- No qualifying trans observations or point totals were identified
Still missing
- Phase-confirmed recessive case data were not identified.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5
PP1 No segregation data were identified for this variant in affected relatives, so PP1 cannot be applied. Details ▾Hide ▴
Rule
AR Condition: Segregation in 1, 2, or >=3 affected relatives for Supporting, Moderate, or Strong.
Evidence considered
- No reported affected-relative segregation information was identified
Still missing
- Family segregation data were not identified.
Sources
BS3 No ATM VCEP-compatible benign functional evidence showing rescue of an ATM-specific feature or radiosensitivity was identified. The available multiplex study instead classified p.(His2788Tyr) as non-functional, so BS3 is not supported and requires no further benign functional weighting at this stage. Details ▾Hide ▴
Rule
Use when a variant rescues both an ATM specific feature AND radiosensitivity for Moderate, or either one for Supporting.
Evidence considered
- Lee et al. 2025 Table S1 lists c.8362C>T p.H2788Y as Non-functional with High confidence
- ATM CSPEC applies BS3 only when a variant rescues an ATM-specific feature and/or radiosensitivity
Still missing
- A validated ATM rescue assay supporting normal function was not identified.
Sources
BP2 No co-occurrence data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
BP2 point-based framework for ATM co-occurrence observations
Evidence considered
- No qualifying BP2 point assignments were identified
Still missing
- Qualifying co-occurrence or homozygous unaffected data were not identified.
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/AThis is a missense variant, and it does not fall into the ATM PVS1 null-variant categories of nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or qualifying exon-level deletion variants. Details ▾Hide ▴
Rule
Use ATM PVS1 Decision Tree
Evidence considered
- NM_000051.4:c.8362C>T corresponds to p.(His2788Tyr)
- pvs1_variant_assessment labels this variant bucket as other and apply_generic_pvs1_framework as false
- ATM CSPEC PVS1 guidance is limited to loss-of-function variant classes
Sources
PS2 N/APS2 is not used in the ATM VCEP framework. Details ▾Hide ▴
PM1 N/APM1 is not used in the ATM VCEP framework. Details ▾Hide ▴
PM4 N/APM4 in the ATM VCEP framework is used for stop-loss variants, and this variant is a missense change. Details ▾Hide ▴
Rule
Use for stop-loss variants.
Evidence considered
- c.8362C>T results in p.(His2788Tyr), a missense substitution
Sources
PM5 N/AATM PM5 is restricted to qualifying truncating or splice variants upstream of p.Arg3047, and this variant is a missense substitution. Details ▾Hide ▴
Rule
Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and qualifying splice variants.
Evidence considered
- ATM PM5 specification applies to frameshifting, truncating, and qualifying splice variants
- c.8362C>T is a missense variant
Sources
PM6 N/APM6 is not used in the ATM VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not used in the ATM VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not used in the ATM VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not used in the ATM VCEP framework. Details ▾Hide ▴
BS2 N/ABS2 is not used in the ATM VCEP framework. Details ▾Hide ▴
BS4 N/ABS4 is not used in the ATM VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not used in the ATM VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not used in the ATM VCEP framework. Details ▾Hide ▴
BP5 N/ABP5 is not used in the ATM VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in the ATM VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 in the ATM VCEP framework is used for synonymous or deep intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, with RNA-based extensions.
Evidence considered
- c.8362C>T results in p.(His2788Tyr), a missense substitution
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.8362C>T
- Protein (HGVS p.)
- NP_000042.3:p.(His2788Tyr)
- GRCh38
- chr11:108343315 C>T
- GRCh37
- chr11:108214042 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
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 REVEL is 0.669, which is below the ATM PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the splicing threshold of >=0.2. These findings do not support PP3. Details ▾Hide ▴
Rule
Missense: REVEL >.7333; Splicing: SpliceAI >=0.2.
Evidence considered
- REVEL score 0.669
- SpliceAI max delta score 0.01
Sources
BP4 REVEL is 0.669, which is above the ATM BP4 missense threshold of <=0.249, so benign missense prediction is not supported. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the benign splicing threshold of <=0.1, but this does not overcome the missense prediction result. Details ▾Hide ▴
Rule
Missense: REVEL <=.249; Splicing: SpliceAI <=0.1.
Evidence considered
- REVEL score 0.669
- SpliceAI max delta score 0.01
Sources
BP7 N/ABP7 in the ATM VCEP framework is used for synonymous or deep intronic variants, and this variant is missense. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants, with RNA-based extensions.
Evidence considered
- c.8362C>T results in p.(His2788Tyr), a missense substitution
Sources
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/3720487/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108214042-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108343315-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.8362…
- OncoKB ↗www.oncokb.org/gene/ATM/H2788Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.8362C%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 has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.