About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.8161G>A, p.(Asp2721Asn)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore 0, which is below the ATM PM2_Supporting threshold of <=0.001%.
PP3Supporting
PP3 · supporting
Available computational evidence supports a damaging missense effect. REVEL is 0.957, which is above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644, also favoring deleteriousness. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, supporting interpretation as a missense effect rather than a splice effect.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
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, PP5 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
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Uncertain significance · 1 Likely pathogenic.
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
10 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53771356, n = 10 times).
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: 3 met · 3 not met · 7 not assessed · 15 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.8161G>A (p.Asp2721Asn; p.D2721N) variant has been observed in somatic cancers (COSMIC COSV53771356, n=10) and has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as Likely Pathogenic.
This variant is absent from both gnomAD v2.1 and gnomAD v4.1, supporting rarity and meeting the ATM PM2_Supporting frequency threshold of <=0.001%.
Available computational evidence supports a damaging missense effect: REVEL is 0.957, above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644; a VCEP-linked supplementary table scored the variant as non-functional with medium-high confidence; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.07.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore 0, which is below the ATM PM2_Supporting threshold of <=0.001%. Details ▾Hide ▴
Rule
ATM PM2_Supporting: frequency <=0.001% in gnomAD v4; a single observation in one subpopulation may still qualify.
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- ATM PM2 threshold is <=0.001% in gnomAD v4
Sources
PP3 SupportingAvailable computational evidence supports a damaging missense effect. REVEL is 0.957, which is above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644, also favoring deleteriousness. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, supporting interpretation as a missense effect rather than a splice effect. Details ▾Hide ▴
Rule
ATM PP3 for missense variants: REVEL >0.7333.
Evidence considered
- REVEL 0.957
- BayesDel 0.0527644
- SpliceAI max delta 0.07
- ATM PP3 missense threshold is REVEL >0.7333
Sources
PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 3 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BA1 threshold of >0.5%. Details ▾Hide ▴
Rule
ATM BA1: grpmax filtering AF >0.5% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1
- ATM BA1 threshold is >0.5%
Sources
BS1 This variant is absent from gnomAD v4.1, so its frequency is 0 and does not meet the ATM BS1 threshold of >0.05%. Details ▾Hide ▴
Rule
ATM BS1: grpmax filtering AF >0.05% in gnomAD v4.
Evidence considered
- Absent from gnomAD v4.1
- ATM BS1 threshold is >0.05%
Sources
BP4 BP4 is not met because the missense predictor threshold is not satisfied: REVEL is 0.957, which is above the ATM BP4 cutoff of <=0.249. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, the damaging missense prediction does not support a benign computational conclusion. Details ▾Hide ▴
Rule
ATM BP4 for missense variants: REVEL <=0.249; splice BP4 requires SpliceAI <=0.1.
Evidence considered
- REVEL 0.957
- SpliceAI max delta 0.07
- ATM BP4 missense threshold is REVEL <=0.249
Sources
Not assessed · 7 · no assessment recorded
PS1 No evidence was identified showing that this variant produces the same amino acid change as an established ATM pathogenic or likely pathogenic variant, and SpliceAI does not suggest an alternative splice-based PS1 scenario for this substitution. Details ▾Hide ▴
Rule
ATM PS1 is used for the same amino acid change or qualifying matched splice events.
Evidence considered
- ATM PS1 requires a qualifying pathogenic comparator
- SpliceAI max delta score is 0.07
Still missing
- No qualifying same-amino-acid pathogenic comparator was identified.
Sources
PS3 No ATM VCEP-approved functional study was identified showing that this variant fails to rescue an ATM-specific function or radiosensitivity. A VCEP-linked supplementary table scored the variant as non-functional, but this was not sufficient on its own to assign PS3 under the ATM functional evidence rules. Details ▾Hide ▴
Rule
ATM PS3 requires failure to rescue ATM-specific function and/or radiosensitivity in approved assays.
Evidence considered
- ATM PS3 requires failed rescue in approved assay framework
- Variant not found in ATM kinase activity or radiosensitivity supplementary assay tables
- Supplementary Table S1 scored c.8161G>A as non-functional with medium-high confidence
Still missing
- No exact-variant kinase rescue or radiosensitivity rescue study meeting ATM VCEP PS3 requirements was identified.
Sources
PS4 This variant has been reported in ClinVar and in somatic cancer databases, but no case-control study or other enrichment data meeting the ATM PS4 threshold were identified. Details ▾Hide ▴
Rule
ATM PS4 requires significant case-control enrichment.
Evidence considered
- ClinVar expert-panel entry exists
- COSMIC reports somatic observations
- No case-control result meeting p-value and effect-size thresholds was identified
Still missing
- No qualifying case-control statistics were identified.
- No validated count of unrelated affected individuals meeting ATM PS4 specifications was identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia, so PM3 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
ATM PM3 is a point-based recessive criterion.
Evidence considered
- ATM PM3 requires point-based trans observations in A-T probands
- No qualifying trans data were identified
Still missing
- No qualifying phase-confirmed or phase-compatible recessive proband data were identified.
Sources
PP1 No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 cannot be assigned. Details ▾Hide ▴
Rule
ATM PP1 uses affected-relative segregation counts for the recessive disorder.
Evidence considered
- ATM PP1 is defined for segregation in affected relatives in the recessive condition
- No segregation evidence was identified
Still missing
- No pedigree-based segregation evidence was identified.
Sources
BS3 No ATM VCEP-approved functional study was identified showing rescue of both an ATM-specific feature and radiosensitivity, or rescue of either one alone, for this variant. Therefore BS3 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
ATM BS3 requires rescue of ATM-specific function and/or radiosensitivity in approved assays.
Evidence considered
- ATM BS3 requires rescue in approved functional assays
- Variant not found in ATM kinase activity or radiosensitivity supplementary assay tables
Still missing
- No exact-variant rescue study meeting ATM VCEP BS3 requirements was identified.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-A-T individual, so BP2 cannot be assigned. Details ▾Hide ▴
Rule
ATM BP2 uses negative points from unaffected non-A-T individuals with confirmed or likely in trans observations.
Evidence considered
- ATM BP2 is a point-based benign trans co-occurrence criterion
- No qualifying trans co-occurrence data were identified
Still missing
- No qualifying benign trans co-occurrence data were identified.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, initiation-codon, exon-level deletion, or canonical +/-1,2 splice variant, so the ATM PVS1 framework does not apply. Details ▾Hide ▴
Rule
ATM PVS1 decision tree applies to loss-of-function variant classes, not this missense substitution.
Evidence considered
- ATM VCEP includes a gene-specific PVS1 framework
- c.8161G>A is a missense substitution
- Generic PVS1 scaffold marked this variant outside default null-variant buckets
Sources
PS2 VCEPThe ATM VCEP marks PS2 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists PS2 as not applicable
Sources
PM1 VCEPThe ATM VCEP marks PM1 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists PM1 as not applicable
Sources
PM4 N/AATM PM4 is specified for stop-loss variants, and this variant is a missense substitution. Details ▾Hide ▴
Rule
ATM PM4: use for stop-loss variants.
Evidence considered
- ATM PM4 is limited to stop-loss variants
- c.8161G>A is a missense variant
Sources
PM5 N/AIn the ATM VCEP framework, PM5 is a truncation-cutoff rule for qualifying truncating or certain splice variants upstream of p.Arg3047, not a classic same-residue missense rule. This missense variant does not meet that rule type. Details ▾Hide ▴
Rule
ATM PM5_Supporting applies to specified truncating or qualifying splice variants upstream of p.Arg3047.
Evidence considered
- ATM PM5 is not a classic same-residue missense rule
- pm5_candidates artifact marked classic PM5 search ineligible
- c.8161G>A is a missense substitution
Sources
cspec ↗pm5_candidates
PM6 VCEPThe ATM VCEP marks PM6 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists PM6 as not applicable
Sources
PP2 VCEPThe ATM VCEP marks PP2 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists PP2 as not applicable
Sources
PP4 VCEPThe ATM VCEP marks PP4 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists PP4 as not applicable
Sources
BS2 VCEPThe ATM VCEP marks BS2 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BS2 as not applicable
Sources
BS4 VCEPThe ATM VCEP marks BS4 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BS4 as not applicable
Sources
BP1 VCEPThe ATM VCEP marks BP1 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BP1 as not applicable
Sources
BP3 VCEPThe ATM VCEP marks BP3 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BP3 as not applicable
Sources
BP5 VCEPThe ATM VCEP marks BP5 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BP5 as not applicable
Sources
BP6 VCEPThe ATM VCEP marks BP6 as not applicable in this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification.
Evidence considered
- ATM VCEP lists BP6 as not applicable
Sources
BP7 N/AATM BP7 is specified for synonymous or deep intronic variants without splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous/deep intronic variants, with RNA subrules when available.
Evidence considered
- ATM BP7 applies to synonymous and deep intronic variants
- c.8161G>A is a missense variant
- SpliceAI max delta 0.07
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.8161G>A
- Protein (HGVS p.)
- NP_000042.3:p.(Asp2721Asn)
- GRCh38
- chr11:108335854 G>A
- GRCh37
- chr11:108206581 G>A
- ClinVar
- 1054111
- COSMIC
- COSV53771356
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in ATM
—
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
- 0.957
- BayesDel
- 0.053
How the predictions were used
PP3 SupportingAvailable computational evidence supports a damaging missense effect. REVEL is 0.957, which is above the ATM PP3 threshold of >0.7333; BayesDel is 0.0527644, also favoring deleteriousness. SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, supporting interpretation as a missense effect rather than a splice effect. Details ▾Hide ▴
Rule
ATM PP3 for missense variants: REVEL >0.7333.
Evidence considered
- REVEL 0.957
- BayesDel 0.0527644
- SpliceAI max delta 0.07
- ATM PP3 missense threshold is REVEL >0.7333
Sources
BP4 BP4 is not met because the missense predictor threshold is not satisfied: REVEL is 0.957, which is above the ATM BP4 cutoff of <=0.249. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07, the damaging missense prediction does not support a benign computational conclusion. Details ▾Hide ▴
Rule
ATM BP4 for missense variants: REVEL <=0.249; splice BP4 requires SpliceAI <=0.1.
Evidence considered
- REVEL 0.957
- SpliceAI max delta 0.07
- ATM BP4 missense threshold is REVEL <=0.249
Sources
BP7 N/AATM BP7 is specified for synonymous or deep intronic variants without splice impact, and this variant is a missense substitution. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous/deep intronic variants, with RNA subrules when available.
Evidence considered
- ATM BP7 applies to synonymous and deep intronic variants
- c.8161G>A is a missense variant
- SpliceAI max delta 0.07
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.957. BayesDel score = 0.0527644.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 21665257 ↗Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.Micol R et al. · 2011No paper-specific finding is recorded.
-
PMID 25122203 ↗The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.Méneret A et al. · 2014No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
-
PMID 29906526 ↗PROMIDISα: A T-cell receptor α signature associated with immunodeficiencies caused by V(D)J recombination defects.Berland A et al. · 2019No paper-specific finding is recorded.
-
PMID 20301317 ↗PMID:20301317No paper-specific finding is recorded.
-
PMID 20301790 ↗Ataxia-Telangiectasia.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 24418350 ↗EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.No paper-specific finding is recorded.
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
-
PMID 20050888 ↗EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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 0.070
Open source ↗
ClinVar
2 Uncertain significance · 1 Likely pathogenic
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/1054111/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108206581-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108335854-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.8161…
- OncoKB ↗www.oncokb.org/gene/ATM/D2721N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105169560
- 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) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 1054111)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.957. BayesDel score = 0.0527644.
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 previously been reported in somatic cancers (COSMIC; COSV53771356, n = 10 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.