About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.67C>T, p.(Arg23Ter)
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 variant is a nonsense change, NM_000051.3:c.67C>T (p.Arg23Ter, p.R23*), that introduces a very early premature stop codon in ATM. The ATM VCEP includes PVS1 guidance, loss of function is an established disease mechanism for ATM, and this early truncating event is consistent with full-strength PVS1 under the ATM PVS1 decision framework.
PM2Supporting
PM2 · supporting
This variant is present in gnomAD v4.1 at AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles) with no homozygotes, which is below the ATM PM2 threshold of 0.001%. This rarity supports PM2 at supporting strength.
PM5Supporting
PM5 · supporting
This variant is a truncating variant with a premature termination codon at p.Arg23, which is far upstream of the ATM PM5 cutoff at p.Arg3047. This meets the ATM-specific PM5 supporting rule for truncating variants.
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
6 / 1,613,346 alleles
gnomAD v4.1: 6 / 1,613,346 alleles. Recorded AF 3.71898e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.98915e-05; MAF= 0.00199%, 5/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.80136e-05; MAF= 0.00980%, 3/30608 alleles, homozygotes = 0); grpmax FAF= 2.596e-05.
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 · 3 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.67C>T (p.Arg23Ter, p.R23*) variant is reported in ClinVar as pathogenic, including a pathogenic expert panel classification, and it also has variant-specific cancer curation in OncoKB.
This variant is rare in population databases, with gnomAD v4.1 AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles; no homozygotes), which is below the ATM PM2 threshold of 0.001%.
In an ATM supplementary SNV table, this variant was categorized as non-functional with medium-high confidence, which is consistent with a damaging loss-of-function effect, although the available summary alone does not establish ATM VCEP PS3 weighting.
This is a nonsense variant predicted to create a very early stop codon; SpliceAI predicts no significant splice impact with a max delta score of 0.00, and the ATM computational PP3/BP4 rules are not used here because they are defined for missense or specified splicing contexts rather than truncating variants.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a nonsense change, NM_000051.3:c.67C>T (p.Arg23Ter, p.R23*), that introduces a very early premature stop codon in ATM. The ATM VCEP includes PVS1 guidance, loss of function is an established disease mechanism for ATM, and this early truncating event is consistent with full-strength PVS1 under the ATM PVS1 decision framework. Details ▾Hide ▴
Rule
ATM VCEP PVS1 decision tree for null variants
Evidence considered
- Nonsense variant p.(Arg23Ter) near the 5' end of the coding sequence
- ATM VCEP PVS1 guidance is available
- ATM loss of function is an established disease mechanism
Sources
PM2 SupportingThis variant is present in gnomAD v4.1 at AF 3.71898e-06 (0.00037%, 6/1,613,346 alleles) with no homozygotes, which is below the ATM PM2 threshold of 0.001%. This rarity supports PM2 at supporting strength. Details ▾Hide ▴
Rule
ATM PM2_Supporting if frequency ≤0.001% in gnomAD v4
Evidence considered
- gnomAD v4.1 total AF 3.71898e-06
- 0 homozygotes
- ATM PM2 threshold ≤0.001%
Sources
PM5 SupportingThis variant is a truncating variant with a premature termination codon at p.Arg23, which is far upstream of the ATM PM5 cutoff at p.Arg3047. This meets the ATM-specific PM5 supporting rule for truncating variants. Details ▾Hide ▴
Rule
ATM PM5_Supporting for truncating variants with premature stop upstream of p.Arg3047
Evidence considered
- Truncating variant p.Arg23Ter
- ATM PM5 truncating-variant rule upstream of p.Arg3047
Sources
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 3 · evaluated, threshold not reached
BA1 This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BA1 threshold of greater than 0.5%. Details ▾Hide ▴
Rule
ATM BA1 if grpmax filtering AF >0.5% in gnomAD v4
Evidence considered
- gnomAD v4.1 AF 3.71898e-06
- ATM BA1 threshold >0.5%
Sources
BS1 This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is far below the ATM BS1 threshold of greater than 0.05%. Details ▾Hide ▴
Rule
ATM BS1 if grpmax filtering AF >0.05% in gnomAD v4
Evidence considered
- gnomAD v4.1 AF 3.71898e-06
- ATM BS1 threshold >0.05%
Sources
BS3 Available evidence does not support BS3. The ATM VCEP requires rescue of an ATM-specific feature and/or radiosensitivity for benign functional evidence, and the available supplementary summary instead categorized this variant as non-functional. Details ▾Hide ▴
Rule
ATM BS3 requires rescue in defined functional assays
Evidence considered
- ATM supplementary SNV table listed c.67C>T as non-functional with medium-high confidence
Still missing
- Direct assay details were not available to determine whether any benign rescue result exists.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
Not assessed · 5 · no assessment recorded
PS3 Variant-specific functional literature and an ATM supplementary SNV table were identified, and the supplementary table categorized this variant as non-functional with medium-high confidence. However, the available summary does not establish the ATM VCEP-required rescue assay result needed to assign PS3 strength. Details ▾Hide ▴
Rule
ATM PS3 requires failed rescue of ATM-specific feature and/or radiosensitivity at defined strength
Evidence considered
- OncoKB listed variant-specific functional literature
- ATM supplementary SNV table listed c.67C>T as non-functional with medium-high confidence
Still missing
- Direct assay details showing whether the variant failed to rescue an ATM-specific feature and/or radiosensitivity were not confirmed.
Sources
PS4 This variant has been reported in ClinVar and in published literature, but no case-control study or exact affected-versus-control enrichment meeting the ATM VCEP PS4 threshold was identified. Available evidence is therefore insufficient to assign PS4. Details ▾Hide ▴
Rule
ATM PS4 requires a qualifying case-control result
Evidence considered
- ClinVar pathogenic submissions and expert panel classification
- Published case references exist
Still missing
- No p-value ≤0.05 with effect size meeting the ATM VCEP threshold was identified for this exact variant.
- Counts of unrelated affected individuals carrying this exact variant were not resolved to an ATM VCEP PS4 rule.
Sources
PM3 No confirmed trans observations, homozygous affected observations, or other point-scored evidence meeting the ATM PM3 framework were identified for this variant. Details ▾Hide ▴
Rule
ATM PM3/BP2 point-based framework
Evidence considered
- ATM PM3 requires point-based trans or homozygous evidence in affected probands
Still missing
- No resolved ATM PM3 point total was available for this exact variant.
- Phase and second-variant status in reported affected individuals were not confirmed.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No segregation data were identified to show this variant tracking with disease in affected relatives under the ATM PP1 framework. Details ▾Hide ▴
Rule
ATM PP1 requires segregation in affected relatives for the relevant recessive condition
Evidence considered
- Published references exist but usable segregation counts were not resolved
Still missing
- No counted affected segregations were confirmed.
- No family-level segregation summary was identified for this exact variant.
Sources
BP2 No unaffected in-trans observations, phase-unknown benign point-scored observations, or homozygous unaffected observations meeting the ATM BP2 framework were identified for this variant. Details ▾Hide ▴
Rule
ATM PM3/BP2 point-based framework
Evidence considered
- ATM BP2 requires point-based co-occurrence evidence
Still missing
- No resolved BP2 point total was available for this exact variant.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AAvailable evidence does not support PS1 because this variant is a nonsense change, and the ATM PS1 specification is directed to missense or defined splicing equivalence scenarios rather than truncating variants such as p.(Arg23Ter). Details ▾Hide ▴
Rule
ATM PS1 specification applies to missense or defined splicing equivalence contexts
Evidence considered
- Variant consequence is nonsense
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 N/AThe ATM VCEP marks PS2 as not applicable in this framework. Details ▾Hide ▴
PM1 N/AThe ATM VCEP marks PM1 as not applicable in this framework. Details ▾Hide ▴
PM4 N/AAvailable evidence does not support PM4 because the ATM VCEP uses PM4 for stop-loss variants, and this variant is a nonsense change. Details ▾Hide ▴
Rule
ATM PM4 is used for stop-loss variants
Evidence considered
- Variant consequence is nonsense
- not stop-loss
Sources
PM6 N/AThe ATM VCEP marks PM6 as not applicable in this framework. Details ▾Hide ▴
PP2 N/AThe ATM VCEP marks PP2 as not applicable in this framework. Details ▾Hide ▴
PP3 N/AAvailable computational evidence was reviewed, including SpliceAI and BayesDel, but the ATM PP3 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
ATM PP3 applies to missense or specified splicing contexts
Evidence considered
- Nonsense variant
- SpliceAI max delta 0.00
- BayesDel score 0.60222
Sources
PP4 N/AThe ATM VCEP marks PP4 as not applicable in this framework. Details ▾Hide ▴
BS2 N/AThe ATM VCEP marks BS2 as not applicable in this framework. Details ▾Hide ▴
BS4 N/AThe ATM VCEP marks BS4 as not applicable in this framework. Details ▾Hide ▴
BP1 N/AThe ATM VCEP marks BP1 as not applicable in this framework. Details ▾Hide ▴
BP3 N/AThe ATM VCEP marks BP3 as not applicable in this framework. Details ▾Hide ▴
BP4 N/AAvailable computational evidence was reviewed, but the ATM BP4 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
ATM BP4 applies to missense or specified splicing contexts
Evidence considered
- Nonsense variant
- SpliceAI max delta 0.00
- BayesDel score 0.60222
Sources
BP5 N/AThe ATM VCEP marks BP5 as not applicable in this framework. Details ▾Hide ▴
BP6 N/AThe ATM VCEP marks BP6 as not applicable in this framework. Details ▾Hide ▴
BP7 N/AAvailable evidence does not support BP7 because this variant is a nonsense coding change rather than a synonymous or qualifying deep intronic variant. Details ▾Hide ▴
Rule
ATM BP7 is for synonymous or qualifying deep intronic variants
Evidence considered
- Variant consequence is nonsense
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.67C>T
- Protein (HGVS p.)
- NP_000042.3:p.(Arg23Ter)
- GRCh38
- chr11:108227691 C>T
- GRCh37
- chr11:108098418 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
6 / 1,613,346 alleles
AF 3.72e-06 · 0 homozygotes · FAF 3.65e-06
gnomAD v2.1
5 / 251,364 alleles
AF 1.99e-05 · 0 homozygotes · FAF 2.6e-05
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,613,346 alleles · 0 hom · FAF 3.7e-06
| South Asian2 / 91,056 | 2.2e-05 |
| European (non-Finnish)4 / 1,179,690 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2e-05 · 5 / 251,364 alleles · 0 hom · FAF 2.6e-05
| South Asian3 / 30,608 | 9.8e-05 |
| European (non-Finnish)2 / 113,672 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71898e-06; MAF= 0.00037%, 6/1613346 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19645e-05; MAF= 0.00220%, 2/91056 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.98915e-05; MAF= 0.00199%, 5/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.80136e-05; MAF= 0.00980%, 3/30608 alleles, homozygotes = 0); grpmax FAF= 2.596e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AAvailable computational evidence was reviewed, including SpliceAI and BayesDel, but the ATM PP3 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
ATM PP3 applies to missense or specified splicing contexts
Evidence considered
- Nonsense variant
- SpliceAI max delta 0.00
- BayesDel score 0.60222
Sources
BP4 N/AAvailable computational evidence was reviewed, but the ATM BP4 rule is defined for missense and specified splicing scenarios rather than nonsense variants such as p.(Arg23Ter). SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
ATM BP4 applies to missense or specified splicing contexts
Evidence considered
- Nonsense variant
- SpliceAI max delta 0.00
- BayesDel score 0.60222
Sources
BP7 N/AAvailable evidence does not support BP7 because this variant is a nonsense coding change rather than a synonymous or qualifying deep intronic variant. Details ▾Hide ▴
Rule
ATM BP7 is for synonymous or qualifying deep intronic variants
Evidence considered
- Variant consequence is nonsense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.
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
6 / 1,613,346 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/232248/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108098418-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108227691-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.67C%…
- OncoKB ↗www.oncokb.org/gene/ATM/R23*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105140813
- 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= 3.71898e-06; MAF= 0.00037%, 6/1613346 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19645e-05; MAF= 0.00220%, 2/91056 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.98915e-05; MAF= 0.00199%, 5/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 9.80136e-05; MAF= 0.00980%, 3/30608 alleles, homozygotes = 0); grpmax FAF= 2.596e-05.
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 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 = 0.00). BayesDel score = 0.60222.
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; COSV53733622, n = 9 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.