About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.2930G>A, p.(Cys977Tyr)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is very rare in population databases. In gnomAD v4.1 the total allele frequency is 0.00025% (4/1,609,362 alleles) and the highest observed subpopulation frequency is 0.00034%, both below the ATM PM2_Supporting threshold of 0.001%.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. The REVEL score is 0.778, which is above the ATM PP3 threshold of 0.7333, and BayesDel is 0.318994. SpliceAI predicts no significant splice impact (max delta score 0.02), so the supporting computational evidence is for missense effect rather than splice disruption.
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; 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
4 / 1,609,362 alleles
gnomAD v4.1: 4 / 1,609,362 alleles. Recorded AF 2.48546e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.39582e-05; MAF= 0.00340%, 1/29448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.9185e-05; MAF= 0.00692%, 1/14454 alleles, homozygotes = 0).
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
6 reported laboratory submissions
4 Likely pathogenic · 1 Uncertain significance · 1 likely pathogenic.
Context only
ClinVar ↗
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53734070, n = 1 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: 2 met · 4 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.2930G>A (p.Cys977Tyr; p.C977Y) variant has been reported in ClinVar, where most submissions classify it as likely pathogenic, although at least one submission classifies it as uncertain significance.
This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 0.00025% (4/1,609,362 alleles) and gnomAD v2.1 showing 0.00340% (1/29,448 alleles), which is below the ATM PM2_Supporting threshold of 0.001%.
Computational evidence supports a damaging missense effect, with REVEL 0.778 above the ATM PP3 threshold of 0.7333 and BayesDel 0.318994, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.02.
No criteria match.
Met · 2
PM2 SupportingThis variant is very rare in population databases. In gnomAD v4.1 the total allele frequency is 0.00025% (4/1,609,362 alleles) and the highest observed subpopulation frequency is 0.00034%, both below the ATM PM2_Supporting threshold of 0.001%. Details ▾Hide ▴
Rule
PM2_Supporting when frequency is ≤0.001% in gnomAD v4
Evidence considered
- gnomAD v4.1 total AF 2.4854569699048445e-06
- gnomAD v4.1 highest subpopulation AF 3.393344633170962e-06
- gnomAD v2.1 total AF 3.395816354251562e-05
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.778, which is above the ATM PP3 threshold of 0.7333, and BayesDel is 0.318994. SpliceAI predicts no significant splice impact (max delta score 0.02), so the supporting computational evidence is for missense effect rather than splice disruption. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants with REVEL >0.7333
Evidence considered
- REVEL score 0.778
- BayesDel score 0.318994
- SpliceAI max delta score 0.02
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This is a missense variant, not a predicted null variant, and the ATM PVS1 framework is intended for loss-of-function events. SpliceAI predicts no significant splice impact for this variant (max delta score 0.02), so the available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
ATM PVS1 decision tree for loss-of-function variants
Evidence considered
- ATM VCEP PVS1 decision framework is applicable to ATM loss-of-function variants
- Generic PVS1 scaffold does not place this variant in a default null-variant bucket
- SpliceAI max delta score 0.02
Still missing
- RNA data were not identified to confirm or exclude a subtle splicing effect beyond the available prediction.
Sources
BA1 This variant does not meet the ATM BA1 threshold. In gnomAD v4.1 the highest observed population frequency is 0.00034%, which is far below the BA1 threshold of more than 0.5%. Details ▾Hide ▴
Rule
BA1 if gnomAD v4 filtering AF is >0.5%
Evidence considered
- gnomAD v4.1 highest observed population AF 3.393344633170962e-06
Sources
BS1 This variant does not meet the ATM BS1 threshold. In gnomAD v4.1 the highest observed population frequency is 0.00034%, which is far below the BS1 threshold of more than 0.05%. Details ▾Hide ▴
Rule
BS1 if gnomAD v4 filtering AF is >0.05%
Evidence considered
- gnomAD v4.1 highest observed population AF 3.393344633170962e-06
Sources
BP4 Benign computational evidence is not supported. Although SpliceAI predicts no significant splice impact (max delta score 0.02, below the BP4 splice threshold of 0.1), the REVEL score is 0.778, which is well above the BP4 missense threshold of 0.249 and instead supports PP3. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL ≤0.249; splice BP4 requires SpliceAI ≤0.1
Evidence considered
- REVEL score 0.778
- SpliceAI max delta score 0.02
Sources
Not assessed · 7 · no assessment recorded
PS1 ATM PS1 can be used for a missense change when a different nucleotide change is already established as pathogenic or likely pathogenic for the same amino acid substitution and splicing is ruled out. SpliceAI for this variant is low (max delta score 0.02), but no qualifying same-amino-acid pathogenic comparator was identified in the available evidence, so PS1 was not assessed. Details ▾Hide ▴
Rule
ATM PS1 missense rule after splicing is ruled out
Evidence considered
- ATM PS1 missense rule requires a same-amino-acid pathogenic comparator
- SpliceAI max delta score 0.02
Still missing
- No pathogenic or likely pathogenic same-amino-acid comparator was identified in the available evidence.
Sources
PS3 ATM PS3 requires variant-specific functional studies showing failure to rescue an ATM-specific feature, with stronger weight requiring failure to rescue both an ATM-specific feature and radiosensitivity. No qualifying variant-specific functional assay evidence was identified for this variant in the available curated sources, so PS3 was not assessed. Details ▾Hide ▴
Rule
ATM PS3_Supporting or PS3_Moderate requires abnormal ATM rescue assay evidence
Evidence considered
- ATM PS3 requires validated ATM-specific functional assay evidence
- No variant-specific reviewed functional evidence identified in the available curated sources
Still missing
- No validated ATM complementation or rescue assay result for this exact variant was identified.
Sources
PS4 ATM PS4 requires case-control evidence with p-value 0.05 or less and effect size at least 2. No qualifying case-control or enrichment data for this exact variant were identified in the available evidence, so PS4 was not assessed. Details ▾Hide ▴
Rule
Case-control studies with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5
Evidence considered
- ATM PS4 requires qualifying case-control evidence
- ClinVar record does not provide qualifying PS4-level case-control data
Still missing
- No exact-variant case-control study
- odds ratio
- hazard ratio
- relative risk
- or qualifying lower confidence interval was identified.
Sources
PM3 ATM PM3 requires observations in trans with a pathogenic variant in individuals with ataxia-telangiectasia and scoring by the ATM PM3/BP2 point framework. No qualifying trans observations or point-based evidence were identified for this variant, so PM3 was not assessed. Details ▾Hide ▴
Rule
ATM PM3 point-based framework for recessive A-T observations
Evidence considered
- ATM PM3/BP2 point-based framework
Still missing
- No confirmed in-trans observations in affected individuals were identified.
- No PM3 point total could be assigned from the available evidence.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 ATM PP1 in this framework requires segregation in affected relatives for the recessive ataxia-telangiectasia phenotype. No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
AR condition: segregation in 1, 2, or ≥3 affected relatives for supporting, moderate, or strong weight
Evidence considered
- ATM PP1 segregation thresholds for AR disease
- No family segregation details identified in the available evidence
Still missing
- No pedigree or meiosis-level segregation data were identified.
Sources
BS3 ATM BS3 requires variant-specific functional studies showing rescue of both an ATM-specific feature and radiosensitivity for moderate weight, or rescue of either for supporting weight. No qualifying benign functional rescue evidence was identified for this variant, so BS3 was not assessed. Details ▾Hide ▴
Rule
ATM BS3_Supporting or BS3_Moderate requires normal rescue assay evidence
Evidence considered
- ATM BS3 requires validated functional rescue evidence
- No variant-specific reviewed functional evidence identified in the available curated sources
Still missing
- No validated ATM rescue assay result supporting preserved function for this exact variant was identified.
Sources
BP2 ATM BP2 requires co-occurrence or homozygosity evidence scored through the ATM PM3/BP2 framework in unaffected or non-ataxia-telangiectasia settings. No qualifying benign co-occurrence evidence was identified for this variant, so BP2 was not assessed. Details ▾Hide ▴
Rule
ATM BP2 point-based framework for benign co-occurrence evidence
Evidence considered
- ATM PM3/BP2 point-based framework
Still missing
- No confirmed co-occurrence or homozygosity data meeting the ATM BP2 point framework were identified.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThe ATM VCEP specification designates PS2 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
PM1 VCEPThe ATM VCEP specification designates PM1 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
PM4 N/AATM applies PM4 to stop-loss variants. This is a missense variant, so PM4 is not applicable. Details ▾Hide ▴
Rule
Use for stop-loss variants
Evidence considered
- ATM PM4 specification limited to stop-loss variants
Sources
PM5 N/AFor ATM, PM5 is a gene-specific truncation or splice-related rule rather than a classic same-residue missense rule. This missense variant does not fit the ATM PM5 rule, so PM5 is not applicable. Details ▾Hide ▴
Rule
ATM PM5_Supporting applies to specified truncating or qualifying splice variants
Evidence considered
- ATM PM5 specification applies to truncating variants upstream of p.Arg3047 or qualifying splice variants
- PM5 candidate review marked classic same-residue PM5 as ineligible for this gene framework
Sources
cspec ↗pm5_candidates
PM6 VCEPThe ATM VCEP specification designates PM6 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
PP2 VCEPThe ATM VCEP specification designates PP2 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
PP4 VCEPThe ATM VCEP specification designates PP4 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
PP5 VCEPThe ATM VCEP specification designates PP5 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BS2 VCEPThe ATM VCEP specification designates BS2 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BS4 VCEPThe ATM VCEP specification designates BS4 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BP1 VCEPThe ATM VCEP specification designates BP1 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BP3 VCEPThe ATM VCEP specification designates BP3 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BP5 VCEPThe ATM VCEP specification designates BP5 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BP6 VCEPThe ATM VCEP specification designates BP6 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable per ATM VCEP specification
Evidence considered
- ATM VCEP applicability table
Sources
BP7 N/AATM BP7 is intended for synonymous or deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous or deep intronic variants, with optional RNA-based upgrades
Evidence considered
- ATM BP7 specification limited to synonymous and deep intronic contexts
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.2930G>A
- Protein (HGVS p.)
- NP_000042.3:p.(Cys977Tyr)
- GRCh38
- chr11:108271259 G>A
- GRCh37
- chr11:108141986 G>A
- ClinVar
- 233765
- COSMIC
- COSV53734070
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
4 / 1,609,362 alleles
AF 2.49e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
1 / 29,448 alleles
AF 3.4e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,609,362 alleles · 0 hom · FAF 7.9e-07
| European (non-Finnish)4 / 1,178,778 | 3.4e-06 |
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.
gnomAD v2.1
AF 3.4e-05 · 1 / 29,448 alleles · 0 hom
| European (non-Finnish)1 / 14,454 | 6.9e-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= 2.48546e-06; MAF= 0.00025%, 4/1609362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39334e-06; MAF= 0.00034%, 4/1178778 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.39582e-05; MAF= 0.00340%, 1/29448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.9185e-05; MAF= 0.00692%, 1/14454 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.778
- BayesDel
- 0.319
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.778, which is above the ATM PP3 threshold of 0.7333, and BayesDel is 0.318994. SpliceAI predicts no significant splice impact (max delta score 0.02), so the supporting computational evidence is for missense effect rather than splice disruption. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants with REVEL >0.7333
Evidence considered
- REVEL score 0.778
- BayesDel score 0.318994
- SpliceAI max delta score 0.02
Sources
BP4 Benign computational evidence is not supported. Although SpliceAI predicts no significant splice impact (max delta score 0.02, below the BP4 splice threshold of 0.1), the REVEL score is 0.778, which is well above the BP4 missense threshold of 0.249 and instead supports PP3. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL ≤0.249; splice BP4 requires SpliceAI ≤0.1
Evidence considered
- REVEL score 0.778
- SpliceAI max delta score 0.02
Sources
BP7 N/AATM BP7 is intended for synonymous or deep intronic variants, or for RNA evidence showing no aberrant splicing in those variant classes. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
ATM BP7 applies to synonymous or deep intronic variants, with optional RNA-based upgrades
Evidence considered
- ATM BP7 specification limited to synonymous and deep intronic contexts
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.778. BayesDel score = 0.318994.
6 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 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.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 31317629 ↗Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests.No paper-specific finding is recorded.
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PMID 34445196 ↗NGS in Hereditary Ataxia: When Rare Becomes Frequent.No paper-specific finding is recorded.
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PMID 35047863 ↗A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk.No paper-specific finding is recorded.
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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
4 / 1,609,362 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
4 Likely pathogenic · 1 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/?term=NM_000051.4%3Ac.2930G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108141986-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108271259-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.2930…
- OncoKB ↗www.oncokb.org/gene/ATM/C977Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105174176
- 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= 2.48546e-06; MAF= 0.00025%, 4/1609362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39334e-06; MAF= 0.00034%, 4/1178778 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.39582e-05; MAF= 0.00340%, 1/29448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.9185e-05; MAF= 0.00692%, 1/14454 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory). (ClinVarID = 233765)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.778. BayesDel score = 0.318994.
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; COSV53734070, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.