About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.7517_7520del, p.(Arg2506ThrfsTer3)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This variant is a frameshift change predicted to truncate ATM as p.(Arg2506ThrfsTer3). ATM loss of function is an established disease mechanism in the ATM VCEP framework, and this truncating event is not at the extreme 3' end, supporting full-strength PVS1.
PM2Supporting
PM2 · supporting
This variant is rare in population databases. In gnomAD v4.1 the overall allele frequency is 5.58e-06 (0.000558%; 9/1,612,790 alleles), which is below the ATM PM2_Supporting threshold of 0.001%, and no homozygotes were reported.
PM5Supporting
PM5 · supporting
The ATM CSPEC allows PM5 at supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant is predicted to truncate the protein at p.Arg2508, which is upstream of p.Arg3047, so PM5_Supporting is met.
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; Rule4 applies.
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
9 / 1,612,790 alleles
gnomAD v4.1: 9 / 1,612,790 alleles. Recorded AF 5.58039e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.98786e-06; MAF= 0.00080%, 2/250380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27955e-05; MAF= 0.00328%, 1/30492 alleles, homozygotes = 0).
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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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: 3 met · 3 not met · 6 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.7517_7520del (p.Arg2506ThrfsTer3) variant has been reported in ClinVar as pathogenic and is cataloged by OncoKB as a likely oncogenic loss-of-function alteration.
This variant is rare in population databases, with an overall allele frequency of 5.58e-06 (9/1,612,790 alleles) in gnomAD v4.1 and 7.99e-06 (2/250,380 alleles) in gnomAD v2.1, supporting rarity.
No variant-specific functional rescue or loss-of-function assay meeting the ATM VCEP PS3 or BS3 requirements was identified.
This frameshift variant is predicted to truncate ATM at p.Arg2508, and the ATM VCEP framework supports PVS1 for qualifying truncating variants; the ATM CSPEC also allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Arg3047.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a frameshift change predicted to truncate ATM as p.(Arg2506ThrfsTer3). ATM loss of function is an established disease mechanism in the ATM VCEP framework, and this truncating event is not at the extreme 3' end, supporting full-strength PVS1. Details ▾Hide ▴
Rule
ATM VCEP PVS1 decision tree for null variants in a gene where loss of function is a known disease mechanism.
Evidence considered
- Frameshift consequence: p.(Arg2506ThrfsTer3)
- ATM is eligible for PVS1 in the official ATM VCEP framework
- ATM PVS1 guidance indicates PVS1 can be applied for qualifying truncating variants
Sources
PM2 SupportingThis variant is rare in population databases. In gnomAD v4.1 the overall allele frequency is 5.58e-06 (0.000558%; 9/1,612,790 alleles), which is below the ATM PM2_Supporting threshold of 0.001%, and no homozygotes were reported. Details ▾Hide ▴
Rule
ATM PM2_Supporting: frequency ≤0.001% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 overall AF 5.580391743500393e-06 (9/1612790)
- homozygotes 0
- gnomAD v2.1 overall AF 7.987858455148174e-06 (2/250380)
Sources
PM5 SupportingThe ATM CSPEC allows PM5 at supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant is predicted to truncate the protein at p.Arg2508, which is upstream of p.Arg3047, so PM5_Supporting is met. Details ▾Hide ▴
Rule
ATM PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047.
Evidence considered
- Variant is a truncating frameshift
- Predicted stop occurs at p.Arg2508
- upstream of p.Arg3047
Sources
cspec ↗pvs1_variant_assessment
Not met · 3 · evaluated, threshold not reached
PS4 This variant has been reported in affected individuals and is listed in ClinVar, but no ATM-specific case-control study was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5, so PS4 is not met. Details ▾Hide ▴
Rule
ATM PS4 requires case-control evidence with p-value ≤0.05 and effect size threshold.
Evidence considered
- ClinVar lists the variant as Pathogenic
- Published case reports exist
- No qualifying ATM case-control study was identified
Still missing
- A qualifying case-control analysis would be needed to apply PS4.
Sources
BA1 The gnomAD v4.1 filtering allele frequency is 3.65e-06 (0.000365%), which is well below the ATM BA1 threshold of >0.5%, so BA1 is not met. Details ▾Hide ▴
Rule
ATM BA1: grpmax filtering AF >0.5% in gnomAD v4.
Evidence considered
- gnomAD v4.1 grpmax filtering AF 3.65e-06
Sources
BS1 The gnomAD v4.1 filtering allele frequency is 3.65e-06 (0.000365%), which is well below the ATM BS1 threshold of >0.05%, so BS1 is not met. Details ▾Hide ▴
Rule
ATM BS1: grpmax filtering AF >0.05% in gnomAD v4.
Evidence considered
- gnomAD v4.1 grpmax filtering AF 3.65e-06
Sources
Not assessed · 6 · no assessment recorded
PS3 No variant-specific functional study was identified that shows failure to rescue an ATM-specific function in a manner meeting the ATM VCEP PS3 rules. Details ▾Hide ▴
Rule
ATM PS3 requires qualifying failure-to-rescue functional evidence.
Evidence considered
- Screened functional literature did not identify a qualifying variant-specific PS3 assay
Still missing
- A qualifying variant-specific ATM functional assay would be needed to apply PS3.
Sources
PM3 Published reports indicate this variant has been observed in individuals with ataxia-telangiectasia, but the available evidence reviewed here does not provide enough case-level phase and scoring detail to assign ATM PM3 points confidently. Details ▾Hide ▴
Rule
ATM PM3 uses a point-based system for recessive disease observations.
Evidence considered
- Case reports exist but point-based PM3 assignment could not be verified from the reviewed evidence
Still missing
- Case-level confirmation of in trans occurrence with a pathogenic or likely pathogenic ATM variant and the corresponding PM3 points.
Sources
cspec ↗vcep_a_t_m___p_m_3___b_p_2___1___5clinvar ↗PMID:12815592 ↗PMID:15039971 ↗PMID:16941484 ↗PMID:17124347 ↗PMID:19691550 ↗
PP1 No segregation data were identified that document this variant segregating with recessive ATM-related disease in the number of affected relatives required by the ATM VCEP PP1 rules. Details ▾Hide ▴
Rule
ATM PP1 for recessive disease requires segregation in affected relatives.
Evidence considered
- No qualifying segregation evidence was identified
Still missing
- Family-level segregation data would be needed to apply PP1.
Sources
BS3 No variant-specific functional study was identified showing rescue of ATM-specific function or radiosensitivity in a manner meeting the ATM VCEP BS3 rules. Details ▾Hide ▴
Rule
ATM BS3 requires qualifying rescue functional evidence.
Evidence considered
- Screened functional literature did not identify a qualifying variant-specific BS3 assay
Still missing
- A qualifying variant-specific rescue assay would be needed to apply BS3.
Sources
BS4 No non-segregation evidence was identified for this variant in families studied for ATM-related disease. Details ▾Hide ▴
Rule
ATM BS4 is not applicable without qualifying family non-segregation evidence.
Evidence considered
- No qualifying non-segregation evidence was identified
Still missing
- Family-level non-segregation data would be needed to apply BS4.
Sources
BP2 No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, so ATM BP2 points could not be assigned. Details ▾Hide ▴
Rule
ATM BP2 uses a point-based framework for benign in trans observations in unaffected individuals.
Evidence considered
- No qualifying benign co-occurrence evidence was identified
Still missing
- Documented co-occurrence in trans in an unaffected individual would be needed to apply BP2.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is intended for the same amino acid change as an established pathogenic variant or for specific splice events with matching reference variants. This frameshift deletion does not meet those circumstances. Details ▾Hide ▴
Rule
ATM PS1 splicing and same-amino-acid framework.
Evidence considered
- Variant is a frameshift deletion rather than the same amino acid substitution as a known pathogenic variant
Sources
cspec ↗vcep_a_t_m___p_s_1___1___5
PS2 N/AThe ATM VCEP marks PS2 as not applicable for this gene specification. Details ▾Hide ▴
PM1 N/AThe ATM VCEP marks PM1 as not applicable for this gene specification. Details ▾Hide ▴
PM4 N/AATM PM4 is specified for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply. Details ▾Hide ▴
Rule
ATM PM4 is for stop-loss variants.
Evidence considered
- Variant consequence is frameshift
- not stop-loss
Sources
PM6 N/AThe ATM VCEP marks PM6 as not applicable for this gene specification. Details ▾Hide ▴
PP2 N/AThe ATM VCEP marks PP2 as not applicable for this gene specification. Details ▾Hide ▴
PP3 N/AATM PP3 is specified for missense variants and certain non-canonical splice-related variants. This exonic frameshift deletion is evaluated primarily under PVS1 rather than PP3. Details ▾Hide ▴
Rule
ATM PP3 is specified for missense and certain splice-prediction contexts.
Evidence considered
- Variant is a frameshift deletion
- SpliceAI predicts splice impact
- but PP3 is not the primary rule for this variant class in ATM
Sources
PP4 N/AThe ATM VCEP marks PP4 as not applicable for this gene specification. Details ▾Hide ▴
PP5 N/AThe ATM VCEP marks PP5 as not applicable for this gene specification. Details ▾Hide ▴
BS2 N/AThe ATM VCEP marks BS2 as not applicable for this gene specification. Details ▾Hide ▴
BP1 N/AThe ATM VCEP marks BP1 as not applicable for this gene specification. Details ▾Hide ▴
BP3 N/AThe ATM VCEP marks BP3 as not applicable for this gene specification. Details ▾Hide ▴
BP4 N/AATM BP4 is specified for missense variants or variants with no predicted splice impact. This frameshift deletion is not that variant class and also has SpliceAI max delta score 1.00 rather than ≤0.1. Details ▾Hide ▴
Rule
ATM BP4 applies to missense variants with REVEL ≤0.249 or variants with SpliceAI ≤0.1.
Evidence considered
- Variant is a frameshift deletion
- SpliceAI max delta score 1.00
Sources
BP5 N/AThe ATM VCEP marks BP5 as not applicable for this gene specification. Details ▾Hide ▴
BP6 N/AThe ATM VCEP marks BP6 as not applicable for this gene specification. Details ▾Hide ▴
BP7 N/AATM BP7 is specified for synonymous and deep intronic variants or for RNA studies showing no aberrant splicing. This variant is an exonic frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 is for synonymous, deep intronic, or qualifying RNA-negative variants.
Evidence considered
- Variant is a frameshift deletion
- not a synonymous or deep intronic change
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.7517_7520del
- Protein (HGVS p.)
- NP_000042.3:p.(Arg2506ThrfsTer3)
- GRCh38
- chr11:108331441 TAGAG>T
- GRCh37
- chr11:108202168 TAGAG>T
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
9 / 1,612,790 alleles
AF 5.58e-06 · 0 homozygotes · FAF 3.65e-06
gnomAD v2.1
2 / 250,380 alleles
AF 7.99e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 5.6e-06 · 9 / 1,612,790 alleles · 0 hom · FAF 3.7e-06
| South Asian2 / 90,960 | 2.2e-05 |
| European (non-Finnish)7 / 1,179,424 | 5.9e-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 8e-06 · 2 / 250,380 alleles · 0 hom
| South Asian1 / 30,492 | 3.3e-05 |
| European (non-Finnish)1 / 113,310 | 8.8e-06 |
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= 5.58039e-06; MAF= 0.00056%, 9/1612790 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19877e-05; MAF= 0.00220%, 2/90960 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.98786e-06; MAF= 0.00080%, 2/250380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27955e-05; MAF= 0.00328%, 1/30492 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AATM PP3 is specified for missense variants and certain non-canonical splice-related variants. This exonic frameshift deletion is evaluated primarily under PVS1 rather than PP3. Details ▾Hide ▴
Rule
ATM PP3 is specified for missense and certain splice-prediction contexts.
Evidence considered
- Variant is a frameshift deletion
- SpliceAI predicts splice impact
- but PP3 is not the primary rule for this variant class in ATM
Sources
BP4 N/AATM BP4 is specified for missense variants or variants with no predicted splice impact. This frameshift deletion is not that variant class and also has SpliceAI max delta score 1.00 rather than ≤0.1. Details ▾Hide ▴
Rule
ATM BP4 applies to missense variants with REVEL ≤0.249 or variants with SpliceAI ≤0.1.
Evidence considered
- Variant is a frameshift deletion
- SpliceAI max delta score 1.00
Sources
BP7 N/AATM BP7 is specified for synonymous and deep intronic variants or for RNA studies showing no aberrant splicing. This variant is an exonic frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
ATM BP7 is for synonymous, deep intronic, or qualifying RNA-negative variants.
Evidence considered
- Variant is a frameshift deletion
- not a synonymous or deep intronic change
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
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
9 / 1,612,790 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/141647/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108202168-TAGAG-T?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108331441-TAGAG-T?datas…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.7517…
- OncoKB ↗www.oncokb.org/gene/ATM/R2506Tfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105145834
- 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= 5.58039e-06; MAF= 0.00056%, 9/1612790 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19877e-05; MAF= 0.00220%, 2/90960 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.98786e-06; MAF= 0.00080%, 2/250380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27955e-05; MAF= 0.00328%, 1/30492 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108796282, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.