About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.5681_5682del, p.(Glu1894AlafsTer9)
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 frameshift, NM_000051.3:c.5681_5682del, predicted to cause p.(Glu1894AlafsTer9) [p.(E1894Afs*9)]. The ATM VCEP includes gene-specific PVS1 guidance, loss of function is an established disease mechanism for ATM, and this truncating change is not at the extreme 3′ end, supporting PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06, 0.00019%; highest observed population AF 1.60149e-05, 0.00160%; 0 homozygotes), which is below the ATM VCEP PM2_Supporting threshold of 0.001%.
PM5Supporting
PM5 · supporting
Under the ATM VCEP framework, PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047. This frameshift produces p.(Glu1894AlafsTer9), 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
3 / 1,612,956 alleles
gnomAD v4.1: 3 / 1,612,956 alleles. Recorded AF 1.85994e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.140 maximum delta
Recorded SpliceAI maximum delta score: 0.140. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions
4 Pathogenic · 1 likely pathogenic.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 NM_000051.3:c.5681_5682del (NP_000042.3:p.(Glu1894AlafsTer9); p.(E1894Afs*9)) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06; 0 homozygotes), which is below the ATM PM2_Supporting threshold of 0.001% and well below the BS1 and BA1 thresholds.
The variant is a frameshift predicted to truncate ATM at codon 1894, and under the ATM VCEP framework this supports PVS1 because loss of function is an established disease mechanism for ATM; the ATM-specific PM5 truncation rule also applies because the premature termination is upstream of p.Arg3047.
SpliceAI predicts no significant splice effect for this variant (maximum delta score 0.14), which is below the ATM PP3 splice threshold of 0.2 and above the BP4 benign splice threshold of 0.1.
No criteria match.
Met · 4
PVS1 Very strongThis variant is a frameshift, NM_000051.3:c.5681_5682del, predicted to cause p.(Glu1894AlafsTer9) [p.(E1894Afs*9)]. The ATM VCEP includes gene-specific PVS1 guidance, loss of function is an established disease mechanism for ATM, and this truncating change is not at the extreme 3′ end, supporting PVS1 at very strong strength. Details ▾Hide ▴
Rule
ATM VCEP PVS1 decision tree for null variants in ATM
Evidence considered
- Frameshift consequence
- Predicted premature termination after 9 altered amino acids
- ATM loss of function established as disease mechanism
- ATM VCEP PVS1 decision tree available
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06, 0.00019%; highest observed population AF 1.60149e-05, 0.00160%; 0 homozygotes), which is below the ATM VCEP PM2_Supporting threshold of 0.001%. Details ▾Hide ▴
Rule
ATM PM2_Supporting if frequency <=0.001% in gnomAD v4
Evidence considered
- Absent from gnomAD v2.1
- 3/1612956 alleles in gnomAD v4.1
- Highest observed population AF 1.60149e-05
- 0 homozygotes
Sources
PM5 SupportingUnder the ATM VCEP framework, PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047. This frameshift produces p.(Glu1894AlafsTer9), which is upstream of p.Arg3047, so PM5 is met at supporting strength. Details ▾Hide ▴
Rule
ATM PM5_Supporting for truncating variants with premature stop upstream of p.Arg3047
Evidence considered
- ATM-specific truncation-cutoff PM5 rule
- Protein consequence p.(Glu1894AlafsTer9) upstream of p.Arg3047
- PM5 candidate review confirms non-classic truncation mode
Sources
cspec ↗pm5_candidates
Not met · 4 · evaluated, threshold not reached
PP3 For ATM, PP3 for splicing requires SpliceAI at least 0.2. This variant has a maximum SpliceAI delta score of 0.14, which is below that threshold, and REVEL/BayesDel are not applicable to this deletion. Details ▾Hide ▴
Rule
ATM PP3 for splicing if SpliceAI >=0.2; missense if REVEL >0.7333
Evidence considered
- SpliceAI max delta 0.14
- ATM PP3 splice threshold >=0.2
- REVEL skipped for non-SNV
- BayesDel skipped for non-SNV
Sources
BA1 The highest observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is far below the ATM BA1 threshold of greater than 0.5%, so BA1 is not met. Details ▾Hide ▴
Rule
ATM BA1 if grpmax filtering AF >0.5% in gnomAD v4
Evidence considered
- gnomAD v4 grpmax FAF 2.8e-07
- ATM BA1 threshold >0.5%
Sources
BS1 The highest observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is below the ATM BS1 threshold of greater than 0.05%, so BS1 is not met. Details ▾Hide ▴
Rule
ATM BS1 if grpmax filtering AF >0.05% in gnomAD v4
Evidence considered
- gnomAD v4 grpmax FAF 2.8e-07
- ATM BS1 threshold >0.05%
Sources
BP4 For ATM, BP4 for splicing requires SpliceAI 0.1 or lower. This variant has a maximum SpliceAI delta score of 0.14, which is above that benign threshold, and REVEL-based missense assessment is not applicable to this deletion. Details ▾Hide ▴
Rule
ATM BP4 for splicing if SpliceAI <=0.1; missense if REVEL <=0.249
Evidence considered
- SpliceAI max delta 0.14
- ATM BP4 splice threshold <=0.1
- Deletion is not a missense variant
Sources
Not assessed · 6 · no assessment recorded
PS3 No variant-specific functional study was identified that showed this exact variant failed to rescue an ATM-specific feature or failed to rescue both an ATM-specific feature and radiosensitivity, which is required by the ATM VCEP framework for PS3. Details ▾Hide ▴
Rule
ATM PS3 requires failure to rescue ATM-specific feature(s), with moderate or supporting strength depending on assay scope
Evidence considered
- ATM PS3 framework requires variant-specific rescue failure evidence
- Curated literature leads were identified but no exact assay result for this variant was retrieved
Still missing
- Direct review of any exact-variant functional assay was not available
Sources
PS4 ClinVar reports this variant in germline disease databases, but no case-control study or quantified enrichment data meeting the ATM VCEP PS4 threshold were identified. Details ▾Hide ▴
Rule
Case-control studies with p<=0.05 and OR/HR/RR >=2 or lower 95% CI >=1.5
Evidence considered
- ClinVar expert-panel and submitter observations
- ATM PS4 requires case-control evidence
Still missing
- No case-control statistics or odds ratio meeting PS4 criteria were retrieved
Sources
PM3 Published and database observations suggest this variant has been seen in individuals with ataxia-telangiectasia, but the retrieved evidence did not establish confirmed in trans occurrence with a pathogenic ATM variant, phase-unknown point totals, or qualifying homozygous evidence needed to score PM3 under the ATM point-based framework. Details ▾Hide ▴
Rule
ATM PM3 point-based scoring for recessive disease observations
Evidence considered
- ATM PM3/BP2 point-based framework
- ClinVar literature leads for exact variant
Still missing
- No confirmed phase or PM3 point total was retrieved
- No qualifying proband-level genotype details were retrieved
Sources
PP1 No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 could not be applied. Details ▾Hide ▴
Rule
ATM PP1 for segregation in affected relatives in autosomal recessive disease
Evidence considered
- ATM PP1 requires segregation in affected relatives for AR disease
Still missing
- No family segregation data retrieved
Sources
BS3 No variant-specific functional study was identified showing this exact variant rescued an ATM-specific feature or radiosensitivity, which is required by the ATM VCEP framework for BS3. Details ▾Hide ▴
Rule
ATM BS3 requires rescue of ATM-specific feature(s) and/or radiosensitivity depending on strength
Evidence considered
- ATM BS3 framework requires rescue evidence
- Curated literature leads were identified but no exact rescue result for this variant was retrieved
Still missing
- Direct review of any exact-variant rescue assay was not available
Sources
BP2 No qualifying evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, so BP2 could not be applied. Details ▾Hide ▴
Rule
ATM BP2 point-based scoring from unaffected trans or homozygous observations
Evidence considered
- ATM BP2 uses the PM3/BP2 point-based framework
Still missing
- No benign co-occurrence or unaffected trans observation retrieved
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis variant is a frameshift deletion and not a missense change or qualifying splice comparator under the ATM PS1 framework, so PS1 does not apply. Details ▾Hide ▴
Rule
ATM PS1 applies to qualifying missense or matched splice-effect comparators
Evidence considered
- Frameshift consequence
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 VCEPPS2 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
PM1 VCEPPM1 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
PM4 N/AThe ATM VCEP reserves PM4 for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply. Details ▾Hide ▴
Rule
ATM PM4 for stop-loss variants only
Evidence considered
- Frameshift consequence
- ATM PM4 rule limited to stop-loss variants
Sources
PM6 VCEPPM6 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
PP2 VCEPPP2 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
PP4 VCEPPP4 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BS2 VCEPBS2 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BS4 VCEPBS4 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BP1 VCEPBP1 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BP3 VCEPBP3 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BP5 VCEPBP5 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BP6 VCEPBP6 is marked not applicable in the ATM VCEP specifications used for this review. Details ▾Hide ▴
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, or RNA studies showing no aberrant splicing. This variant is a frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 for synonymous/deep intronic variants or RNA evidence of no splice defect
Evidence considered
- Frameshift consequence
- ATM BP7 framework scope
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.5681_5682del
- Protein (HGVS p.)
- NP_000042.3:p.(Glu1894AlafsTer9)
- GRCh38
- chr11:108307900 CAG>C
- GRCh37
- chr11:108178627 CAG>C
- ClinVar
- 407525
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
3 / 1,612,956 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,612,956 alleles · 0 hom · FAF 2.8e-07
| Remaining individuals1 / 62,442 | 1.6e-05 |
| European (non-Finnish)2 / 1,179,252 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: 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= 1.85994e-06; MAF= 0.00019%, 3/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60149e-05; MAF= 0.00160%, 1/62442 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For ATM, PP3 for splicing requires SpliceAI at least 0.2. This variant has a maximum SpliceAI delta score of 0.14, which is below that threshold, and REVEL/BayesDel are not applicable to this deletion. Details ▾Hide ▴
Rule
ATM PP3 for splicing if SpliceAI >=0.2; missense if REVEL >0.7333
Evidence considered
- SpliceAI max delta 0.14
- ATM PP3 splice threshold >=0.2
- REVEL skipped for non-SNV
- BayesDel skipped for non-SNV
Sources
BP4 For ATM, BP4 for splicing requires SpliceAI 0.1 or lower. This variant has a maximum SpliceAI delta score of 0.14, which is above that benign threshold, and REVEL-based missense assessment is not applicable to this deletion. Details ▾Hide ▴
Rule
ATM BP4 for splicing if SpliceAI <=0.1; missense if REVEL <=0.249
Evidence considered
- SpliceAI max delta 0.14
- ATM BP4 splice threshold <=0.1
- Deletion is not a missense variant
Sources
BP7 N/ABP7 is intended for synonymous or qualifying deep intronic variants, or RNA studies showing no aberrant splicing. This variant is a frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 for synonymous/deep intronic variants or RNA evidence of no splice defect
Evidence considered
- Frameshift consequence
- ATM BP7 framework scope
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
9 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
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PMID 27413114 ↗ATM Mutations in Cancer: Therapeutic Implications.No paper-specific finding is recorded.
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PMID 30348496 ↗Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.No paper-specific finding is recorded.
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PMID 30553448 ↗Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.No paper-specific finding is recorded.
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PMID 23807571 ↗Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.Huang Y et al. · 2013No paper-specific finding is recorded.
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PMID 25614872 ↗Ten new ATM alterations in Polish patients with ataxia-telangiectasia.Podralska MJ et al. · 2014No paper-specific finding is recorded.
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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 26896183 ↗Longitudinal analysis of the neurological features of ataxia-telangiectasia.Jackson TJ et al. · 2016No 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
3 / 1,612,956 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.140
Open source ↗
ClinVar
4 Pathogenic · 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/407525/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108178627-CAG-C?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108307900-CAG-C?dataset…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.5681…
- OncoKB ↗www.oncokb.org/gene/ATM/E1894Afs*9
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.5681_5682del
- 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= 1.85994e-06; MAF= 0.00019%, 3/1612956 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60149e-05; MAF= 0.00160%, 1/62442 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 407525)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.