About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.8419-7T>G, p.?
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
NM_000051.4:c.8419-7T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0%), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% in gnomAD v4.
PP3Supporting
PP3 · supporting
SpliceAI predicts a strong splice impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), exceeding the ATM VCEP PP3_Supporting threshold of ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites. PP3 for splice predictions is applied independently here as PVS1 is not met. The variant is located 7 bases upstream of the exon 58 acceptor site, where SpliceAI predicts acceptor loss.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.900 maximum delta
Recorded SpliceAI maximum delta score: 0.900. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 11 not met · 0 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
NM_000051.4:c.8419-7T>G is located 7 bases upstream of the exon 58 acceptor site in ATM and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_Supporting).
SpliceAI predicts a strong splicing impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), meeting the ATM VCEP PP3_Supporting threshold for intronic variants outside canonical splice sites (PP3_Supporting).
The variant is outside the canonical +/-1,2 splice acceptor consensus, and no RNA-based evidence of aberrant splicing is available; PVS1 is therefore not met under the ATM VCEP PVS1 decision tree.
No functional studies, segregation data, case-control data, or variant-specific literature are available. ClinVar classifies this variant as Uncertain significance (1 submitter, ClinVarID 3325300).
No criteria match.
Met · 2
PM2 SupportingNM_000051.4:c.8419-7T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0%), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% in gnomAD v4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0.0%)
- Absent from gnomAD v4.1 (AF = 0.0%)
- Absent from gnomAD-Canada v1.0 (AF = 0.0%)
Sources
PP3 SupportingSpliceAI predicts a strong splice impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), exceeding the ATM VCEP PP3_Supporting threshold of ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites. PP3 for splice predictions is applied independently here as PVS1 is not met. The variant is located 7 bases upstream of the exon 58 acceptor site, where SpliceAI predicts acceptor loss. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.90 (≥0.2 threshold met)
- DS_AL = 0.90 (acceptor loss)
- DS_AG = 0.86 (acceptor gain)
- Variant at c.8419-7
- outside donor/acceptor +/-1
- 2 dinucleotide positions
Still missing
- RNA studies to confirm predicted acceptor loss
Sources
Not met · 11 · evaluated, threshold not reached
PVS1 Variant is located at c.8419-7 (7 bases upstream of exon 58 acceptor site), which is outside the canonical +/-1,2 splice acceptor consensus. The ATM VCEP PVS1 framework permits PVS1(RNA) only when RNA-based evidence of aberrant splicing is available; no such data exist for this variant. SpliceAI prediction alone does not satisfy PVS1 requirements under the ATM VCEP decision tree. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.90 (DS_AL=0.90
- DS_AG=0.86) indicates predicted acceptor loss
- Variant at c.8419-7 is outside canonical +/-1
- 2 splice acceptor consensus
- No RNA-based functional data available
Still missing
- RNA studies to confirm or exclude aberrant splicing at exon 58 acceptor
Sources
PS1 Per the ATM VCEP PS1 Splicing table, for variants located outside the donor/acceptor +/-1,2 dinucleotide positions the baseline predictive code is PP3. PS1 requires a known pathogenic/likely pathogenic reference variant at the same nucleotide or within the same donor/acceptor motif with a matching or weaker splice prediction. No such comparator variant has been identified for c.8419-7T>G. Details ▾Hide ▴
Evidence considered
- Variant at c.8419-7 is outside +/-1
- 2 dinucleotide positions per ATM PS1 Splicing table
- No P/LP reference variant identified at the same nucleotide or within the same acceptor motif
Still missing
- Identification of a P/LP comparator variant at the c.8419 acceptor motif with matching splice prediction
Sources
vcep_atm_ps1_1_5
PS3 No variant-specific functional studies are available. The ATM VCEP PS3/BS3 calibration tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) list approved kinase activity and radiosensitivity assays but this variant has not been tested in any of them. The Suppl_TableS1 (PMID 40580951) systematic functional screen does not include c.8419-7T>G. Details ▾Hide ▴
Evidence considered
- Variant absent from VCEP-approved functional assay calibration tables
- Variant not included in high-throughput functional screen (Suppl_TableS1
- PMID 40580951)
Still missing
- ATM kinase activity assay in ATM-null cells
- Radiosensitivity rescue assay
Sources
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951
PS4 No case-control studies or proband enrichment data are available for this variant. The sole literature source (PMID 25394175) is a practice guideline that does not mention NM_000051.4:c.8419-7T>G. Details ▾Hide ▴
Evidence considered
- No case-control study identified
- PMID 25394175 does not mention the variant
Still missing
- Case-control association study for this variant
Sources
PP1 No segregation data are available for this variant. The ATM VCEP PP1 rule requires segregation analysis in families with ataxia-telangiectasia (AR condition); no such studies have been reported. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified
Still missing
- Segregation analysis in A-T families
BA1 The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BA1 Stand Alone threshold of >0.5%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (grpmax FAF = 0.0%
- threshold >0.5% not met)
Sources
BS1 The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BS1 Strong threshold of >0.05%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (grpmax FAF = 0.0%
- threshold >0.05% not met)
Sources
BS3 No functional studies demonstrating rescue of ATM-specific features or radiosensitivity are available. The ATM VCEP BS3 calibration tables list approved assays but this variant has not been tested. The Suppl_TableS1 (PMID 40580951) high-throughput functional screen does not include c.8419-7T>G. Details ▾Hide ▴
Evidence considered
- Variant not tested in VCEP-approved functional assays
- Variant absent from Suppl_TableS1 systematic functional classification (PMID 40580951)
Still missing
- Functional rescue experiments in ATM-null cells
Sources
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951
BP2 No proband data are available to score against the ATM PM3/BP2 table. The variant has not been reported in any A-T-affected individuals or unaffected individuals with a second ATM pathogenic variant. Without proband observations, no BP2 points can be assigned. Details ▾Hide ▴
Evidence considered
- No A-T probands identified with this variant in trans with a P/LP variant
- No unaffected individuals identified with this variant in trans with a P/LP variant
Still missing
- Proband observations in A-T cohort or unaffected population screening
Sources
vcep_atm_pm3_bp2_1_5
BP4 SpliceAI predicts strong splice impact (max delta = 0.90), far exceeding the ATM VCEP BP4 Supporting threshold of ≤0.1 for benign splicing prediction. This criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.90 (threshold ≤0.1 not met)
- SpliceAI predicts acceptor loss (DS_AL = 0.90)
Sources
PS5 This criterion is not part of the ATM VCEP HBOP v1.5.0 specification. Under generic ACMG/AMP, PS5 requires a reputable source to have reported the variant as pathogenic with evidence not independently available. ClinVar classifies this variant as Uncertain significance (1 star, criteria provided single submitter), not pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain significance (ClinVarID 3325300
- 1 submitter)
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPVCEP HBOP v1.5.0 specifies de novo criteria (PS2/PM6) are not used for ATM; informative de novo occurrences have not been observed and de novo autosomal recessive conditions are unlikely to be informed by phase. Details ▾Hide ▴
PM1 VCEPVCEP HBOP v1.5.0 specifies PM1 is not applicable for ATM; benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time. Details ▾Hide ▴
PM3 N/AThis is an intronic substitution assessed in a case without proband data for ATM recessive disease (ataxia-telangiectasia); PM3 is trivially not applicable in this context. Details ▾Hide ▴
Evidence considered
- No proband data available for PM3 scoring
PM4 N/AVCEP HBOP v1.5.0 specifies PM4 is used only for stop-loss variants. NM_000051.4:c.8419-7T>G is an intronic substitution, not a stop-loss variant. Details ▾Hide ▴
PM5 N/AThe ATM VCEP PM5 rule applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) has been applied with high-quality observed splicing impact and NMD-prone outcome. This is an intronic substitution at c.8419-7 without PVS1(RNA) applied. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.8419-7T>G)
- not a frameshift/truncation
- PVS1(RNA) has not been applied
Sources
cspec ↗pm5_candidates
PM6 VCEPVCEP HBOP v1.5.0 specifies de novo criteria (PS2/PM6) are not used for ATM; informative de novo occurrences have not been observed and de novo autosomal recessive conditions are unlikely to be informed by phase. Details ▾Hide ▴
PP2 VCEPVCEP HBOP v1.5.0 specifies PP2 is not applicable for ATM; ATM does not have a defined low rate of missense benign variation. Details ▾Hide ▴
PP4 VCEPVCEP HBOP v1.5.0 specifies PP4 is not applicable; for autosomal dominant breast cancer, multiple genetic etiologies preclude phenotype specificity; for autosomal recessive A-T, this evidence is built into the PM3/BP2 table. Details ▾Hide ▴
PP5 VCEPVCEP HBOP v1.5.0 designates PP5 as not applicable for this VCEP. Details ▾Hide ▴
BS2 VCEPVCEP HBOP v1.5.0 designates BS2 as not applicable for this VCEP. Details ▾Hide ▴
BS4 VCEPVCEP HBOP v1.5.0 designates BS4 as not applicable for this VCEP. Details ▾Hide ▴
BP1 VCEPVCEP HBOP v1.5.0 designates BP1 as not applicable for this VCEP. Details ▾Hide ▴
BP3 VCEPVCEP HBOP v1.5.0 specifies BP3 is not applicable for ATM; in-frame deletions/insertions in repetitive regions are not relevant to this intronic substitution. Details ▾Hide ▴
BP5 VCEPVCEP HBOP v1.5.0 specifies BP5 is not applicable for ATM; cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population. Details ▾Hide ▴
BP6 VCEPVCEP HBOP v1.5.0 specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/AThe ATM VCEP BP7 prediction-based rule applies only to deep intronic variants further than -21 from the acceptor site; this variant is at -7, which does not qualify. BP7(RNA) requires RNA evidence demonstrating absence of aberrant splicing, which is not available. Details ▾Hide ▴
Evidence considered
- Variant at c.8419-7 is not further than -21 from the acceptor site
- No RNA data available to support BP7(RNA)
Still missing
- RNA studies to assess splicing outcome
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.8419-7T>G
- Protein (HGVS p.)
- NP_000042.3:p.?
- GRCh38
- chr11:108345736 T>G
- GRCh37
- chr11:108216463 T>G
- ClinVar
- 3325300
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSpliceAI predicts a strong splice impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), exceeding the ATM VCEP PP3_Supporting threshold of ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites. PP3 for splice predictions is applied independently here as PVS1 is not met. The variant is located 7 bases upstream of the exon 58 acceptor site, where SpliceAI predicts acceptor loss. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.90 (≥0.2 threshold met)
- DS_AL = 0.90 (acceptor loss)
- DS_AG = 0.86 (acceptor gain)
- Variant at c.8419-7
- outside donor/acceptor +/-1
- 2 dinucleotide positions
Still missing
- RNA studies to confirm predicted acceptor loss
Sources
BP4 SpliceAI predicts strong splice impact (max delta = 0.90), far exceeding the ATM VCEP BP4 Supporting threshold of ≤0.1 for benign splicing prediction. This criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.90 (threshold ≤0.1 not met)
- SpliceAI predicts acceptor loss (DS_AL = 0.90)
Sources
BP7 N/AThe ATM VCEP BP7 prediction-based rule applies only to deep intronic variants further than -21 from the acceptor site; this variant is at -7, which does not qualify. BP7(RNA) requires RNA evidence demonstrating absence of aberrant splicing, which is not available. Details ▾Hide ▴
Evidence considered
- Variant at c.8419-7 is not further than -21 from the acceptor site
- No RNA data available to support BP7(RNA)
Still missing
- RNA studies to assess splicing outcome
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.90).
1 paper record 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 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. · 2015This is a practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors providing referral indications for cancer predisposition assessment. It discusses general criteria for referring patients to cancer genetic consultation across multiple hereditary cancer syndromes.Does not name this variant
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 0.900
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC 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/3325300/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108216463-T-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108345736-T-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108345736-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.8419…
- OncoKB ↗www.oncokb.org/gene/ATM/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.8419-7T%3EG
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3325300)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.90).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).