About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.5515C>T, p.(Gln1839Ter)
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: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong
This nonsense variant introduces a premature termination codon at p.Gln1839Ter (p.Q1839*), well upstream of the 3' end of ATM, and ATM loss of function is an established disease mechanism in the applicable ATM VCEP framework. The ATM PVS1 guidance supports full-strength PVS1 for a truncating variant of this type.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an overall allele frequency of 8.674886328007367e-06 (0.00087%; 14/1613854 alleles) with 0 homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%. This supports PM2 at supporting strength.
PM5Supporting
PM5 · supporting
The ATM VCEP specifies PM5_Supporting for truncating variants with a premature termination codon upstream of p.Arg3047. This variant creates p.Gln1839Ter, which is upstream of p.Arg3047, so PM5 is met at supporting strength.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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: PVS1 very strong, PM2 supporting, PM5 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
14 / 1,613,854 alleles
gnomAD v4.1: 14 / 1,613,854 alleles. Recorded AF 8.67489e-06. Recorded homozygote count 0.
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.
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
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: 4 met · 4 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.5515C>T (p.Gln1839Ter; p.Q1839*) variant has been reported in ClinVar as pathogenic, including expert panel review.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 0.00087% (14/1613854 alleles) with no homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%.
This nonsense variant introduces a premature stop codon at residue 1839, and the ATM VCEP PVS1 framework supports loss of function as a disease mechanism for ATM.
SpliceAI predicts no strong splice effect for this variant (max delta score 0.16), which is below the ATM PP3 splicing threshold of 0.2 and above the BP4 threshold of 0.1, so computational evidence does not independently change the interpretation.
No criteria match.
Met · 4
PVS1 Very strongThis nonsense variant introduces a premature termination codon at p.Gln1839Ter (p.Q1839*), well upstream of the 3' end of ATM, and ATM loss of function is an established disease mechanism in the applicable ATM VCEP framework. The ATM PVS1 guidance supports full-strength PVS1 for a truncating variant of this type. Details ▾Hide ▴
Rule
ATM VCEP PVS1 decision tree for null variants in ATM
Evidence considered
- ATM-specific PVS1 decision framework
- ATM loss-of-function disease mechanism
- nonsense consequence
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at an overall allele frequency of 8.674886328007367e-06 (0.00087%; 14/1613854 alleles) with 0 homozygotes, which is below the ATM PM2_Supporting threshold of 0.001%. This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
ATM PM2_Supporting: frequency ≤0.001% in gnomAD v4
Evidence considered
- gnomAD v2.1 absence
- gnomAD v4.1 rarity threshold
Sources
PM5 SupportingThe ATM VCEP specifies PM5_Supporting for truncating variants with a premature termination codon upstream of p.Arg3047. This variant creates p.Gln1839Ter, which is upstream of p.Arg3047, so PM5 is met at supporting strength. Details ▾Hide ▴
Rule
ATM PM5_Supporting for truncating variants upstream of p.Arg3047
Evidence considered
- ATM truncating-variant PM5 rule
- protein position p.Gln1839Ter
Sources
Not met · 4 · evaluated, threshold not reached
PP3 SpliceAI predicts a maximum delta score of 0.16, which is below the ATM PP3 splicing threshold of 0.2. REVEL is not available because this is not a missense variant, and the available BayesDel score does not substitute for the ATM VCEP PP3 rule. PP3 is therefore not met. Details ▾Hide ▴
Rule
ATM PP3: missense REVEL >0.7333 or splicing SpliceAI ≥0.2 in eligible variant classes
Evidence considered
- SpliceAI score 0.16
- absence of REVEL for nonsense variant
- ATM PP3 thresholds
Sources
BA1 The gnomAD v4.1 frequency for this variant is 0.00087%, which is far below the ATM BA1 threshold of greater than 0.5%. BA1 is not met. Details ▾Hide ▴
Rule
ATM BA1: grpmax filtering AF >0.5% in gnomAD v4
Evidence considered
- gnomAD v4.1 frequency
- ATM BA1 threshold
Sources
BS1 The highest observed frequency remains well below the ATM BS1 threshold of greater than 0.05% in gnomAD v4. Available population data do not support BS1. Details ▾Hide ▴
Rule
ATM BS1: grpmax filtering AF >0.05% in gnomAD v4
Evidence considered
- gnomAD v4.1 rarity
- ATM BS1 threshold
Sources
BP4 SpliceAI predicts a maximum delta score of 0.16, which is above the ATM BP4 no-splice-impact threshold of 0.1. The missense-based REVEL rule is not applicable to this nonsense variant. BP4 is therefore not met. Details ▾Hide ▴
Rule
ATM BP4: missense REVEL ≤0.249 or splicing SpliceAI ≤0.1 in eligible variant classes
Evidence considered
- SpliceAI score 0.16
- ATM BP4 thresholds
Sources
Not assessed · 6 · no assessment recorded
PS3 Published studies reviewed describe ATM loss of function and radiosensitivity in affected cells more broadly, but no validated variant-specific rescue assay was identified for this variant. The ATM VCEP also notes that phenotypic evidence such as deficient ATM activity in patient cells should not be used alone as functional evidence for PS3. Details ▾Hide ▴
Rule
ATM PS3 requires failure to rescue ATM-specific function and/or radiosensitivity in appropriate assays
Evidence considered
- ATM PS3/BS3 rule text
- reviewed ATM functional literature
Still missing
- No variant-specific rescue assay result was identified.
- No ATM-specific functional assay meeting the VCEP PS3 requirements was identified for this exact variant.
Sources
PS4 This variant has been reported in ClinVar, but no case-control study, odds ratio, or exact-variant enrichment statistic meeting the ATM PS4 requirement was identified. Available evidence does not establish PS4 at this time. Details ▾Hide ▴
Rule
ATM PS4 requires case-control evidence with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5
Evidence considered
- ClinVar observations
- ATM PS4 rule
Still missing
- No qualifying case-control statistic was identified.
- No exact-variant enrichment analysis meeting the ATM PS4 threshold was identified.
Sources
PM3 No confirmed observations of this variant in trans with a pathogenic ATM variant in an affected individual were identified, so PM3 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
ATM PM3 point system
Evidence considered
- ATM PM3 point-based framework
- available case-level summaries
Still missing
- No phased in trans observation was identified.
- No qualifying proband scoring information was identified under the ATM PM3 point system.
Sources
vcep_atm_pm3_bp2_1_5clinvar ↗
PP1 No segregation data were identified for this variant, so PP1 cannot be assigned. The available evidence does not show segregation with an ATM-related recessive phenotype in informative relatives. Details ▾Hide ▴
Rule
ATM PP1 requires segregation in affected relatives for the recessive condition
Evidence considered
- ATM PP1 segregation thresholds
- available case summaries
Still missing
- No informative family segregation data were identified.
- No count of affected segregations meeting ATM PP1 thresholds was identified.
Sources
BS3 No variant-specific assay showing rescue of ATM-specific function or radiosensitivity was identified. Available evidence does not support BS3 for this variant. Details ▾Hide ▴
Rule
ATM BS3 requires rescue of ATM-specific function and/or radiosensitivity in appropriate assays
Evidence considered
- ATM BS3 rule text
- reviewed ATM functional literature
Still missing
- No qualifying rescue assay was identified for this exact variant.
Sources
BP2 No confirmed co-occurrence of this variant in trans with a pathogenic ATM variant in an unaffected individual was identified, so BP2 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
ATM BP2 point system
Evidence considered
- ATM BP2 point-based framework
- available case-level summaries
Still missing
- No qualifying unaffected in trans co-occurrence data were identified.
- No ATM BP2 point total could be established.
Sources
vcep_atm_pm3_bp2_1_5clinvar ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AATM PS1 guidance is written for missense changes producing the same amino acid substitution or for splice variants with the same predicted or observed splice event. This variant is a nonsense substitution, so PS1 does not apply. Details ▾Hide ▴
Rule
ATM PS1 specification
Evidence considered
- ATM PS1 missense/splicing rules
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 N/APS2 is marked not applicable in the ATM VCEP specification, so de novo evidence is not used under this framework. Details ▾Hide ▴
PM1 N/APM1 is marked not applicable in the ATM VCEP specification, so hotspot or critical-domain localization is not used as PM1 evidence in this framework. Details ▾Hide ▴
PM4 N/AATM PM4 is specified for stop-loss variants. This variant is a nonsense change, so PM4 does not apply. Details ▾Hide ▴
PM6 N/APM6 is marked not applicable in the ATM VCEP specification, so assumed de novo evidence is not used under this framework. Details ▾Hide ▴
PP2 N/APP2 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
PP4 N/APP4 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BS2 N/ABS2 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BS4 N/ABS4 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BP1 N/ABP1 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BP3 N/ABP3 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BP5 N/ABP5 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BP6 N/ABP6 is marked not applicable in the ATM VCEP specification. Details ▾Hide ▴
BP7 N/ABP7 is specified for synonymous and deep intronic variants. This variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous and deep intronic variants
Evidence considered
- ATM BP7 rule
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.5515C>T
- Protein (HGVS p.)
- NP_000042.3:p.(Gln1839Ter)
- GRCh38
- chr11:108304693 C>T
- GRCh37
- chr11:108175420 C>T
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
14 / 1,613,854 alleles
AF 8.67e-06 · 0 homozygotes · FAF 6.89e-06
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 8.7e-06 · 14 / 1,613,854 alleles · 0 hom · FAF 6.9e-06
| European (non-Finnish)14 / 1,179,904 | 1.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.67489e-06; MAF= 0.00087%, 14/1613854 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.18654e-05; MAF= 0.00119%, 14/1179904 alleles, homozygotes = 0); grpmax FAF= 6.89e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts a maximum delta score of 0.16, which is below the ATM PP3 splicing threshold of 0.2. REVEL is not available because this is not a missense variant, and the available BayesDel score does not substitute for the ATM VCEP PP3 rule. PP3 is therefore not met. Details ▾Hide ▴
Rule
ATM PP3: missense REVEL >0.7333 or splicing SpliceAI ≥0.2 in eligible variant classes
Evidence considered
- SpliceAI score 0.16
- absence of REVEL for nonsense variant
- ATM PP3 thresholds
Sources
BP4 SpliceAI predicts a maximum delta score of 0.16, which is above the ATM BP4 no-splice-impact threshold of 0.1. The missense-based REVEL rule is not applicable to this nonsense variant. BP4 is therefore not met. Details ▾Hide ▴
Rule
ATM BP4: missense REVEL ≤0.249 or splicing SpliceAI ≤0.1 in eligible variant classes
Evidence considered
- SpliceAI score 0.16
- ATM BP4 thresholds
Sources
BP7 N/ABP7 is specified for synonymous and deep intronic variants. This variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous and deep intronic variants
Evidence considered
- ATM BP7 rule
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). BayesDel score = 0.652534.
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
14 / 1,613,854 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
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/189177/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108175420-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108304693-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.5515…
- OncoKB ↗www.oncokb.org/gene/ATM/Q1839*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105144495
- 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= 8.67489e-06; MAF= 0.00087%, 14/1613854 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.18654e-05; MAF= 0.00119%, 14/1179904 alleles, homozygotes = 0); grpmax FAF= 6.89e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic 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 = 0.16). BayesDel score = 0.652534.
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 previously been reported in somatic cancers (COSMIC; COSV53732966, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.