About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.4110_4111delinsAA, p.(Asp1371Asn)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting threshold of allele frequency ≤0.001% in gnomAD v4.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact for this variant (max delta score 0.01 ≤ 0.1 threshold), meeting the VCEP BP4 splicing rule. REVEL score is not available for this indel variant, so the missense-specific BP4 rule cannot be assessed. The SpliceAI result confirms no cryptic splice alteration, which is a valid line of benign computational evidence.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
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: 2 met · 9 not met · 0 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2_Supporting under the ATM VCEP v1.5 threshold of ≤0.001%.
SpliceAI predicts no splice impact (max delta 0.01), meeting BP4_Supporting under the ATM VCEP v1.5 splicing threshold of ≤0.1. REVEL is unavailable for this indel variant.
The same amino acid change p.(Asp1371Asn) exists via c.4111G>A, classified as Uncertain Significance in ClinVar. The VCEP functional supplement (Suppl_TableS1, PMID 40580951) computationally predicts the D1371N change as 'Functional' via DeepATM, but this does not constitute experimental functional evidence for PS3 or BS3.
One pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) are met. Per ACMG/AMP 2015 combination rules (Rule31), >=1 benign supporting and >=1 pathogenic supporting results in Uncertain Significance with conflicting evidence.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting threshold of allele frequency ≤0.001% in gnomAD v4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
- Frequency 0 ≤ VCEP PM2_Supporting threshold of 0.001%
Sources
BP4 SupportingSpliceAI predicts no significant splice impact for this variant (max delta score 0.01 ≤ 0.1 threshold), meeting the VCEP BP4 splicing rule. REVEL score is not available for this indel variant, so the missense-specific BP4 rule cannot be assessed. The SpliceAI result confirms no cryptic splice alteration, which is a valid line of benign computational evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 ≤ BP4 splicing threshold of 0.1
- No predicted splice donor/acceptor gain or loss
Still missing
- REVEL score unavailable for indel — protein-level benign computational evidence not assessed
Sources
Not met · 9 · evaluated, threshold not reached
PS1 The same amino acid change p.(Asp1371Asn) exists via c.4111G>A (a single-nucleotide missense variant), but this comparator is classified as Uncertain Significance in ClinVar, not Pathogenic or Likely Pathogenic. PS1 requires a previously established pathogenic variant with the same amino acid change. SpliceAI confirms no cryptic splice impact for the variant under assessment (max delta 0.01). Details ▾Hide ▴
Evidence considered
- c.4111G>A produces same D1371N amino acid change but is ClinVar VUS
- not pathogenic
- SpliceAI max delta 0.01 — no splicing concern for either variant
Sources
PS3 No experimental functional data (rescue assays for ATM-specific phosphorylation or radiosensitivity) has been identified for this variant or for the same amino acid change D1371N. The VCEP Suppl_TableS1 (PMID 40580951) includes a computational DeepATM prediction for c.4111G>A (D1371N) classified as 'Functional', but this is a predictive score, not experimental functional evidence meeting PS3 requirements. Details ▾Hide ▴
Evidence considered
- DeepATM computational prediction for D1371N via c.4111G>A classifies as 'Functional' (combined_score=0.046)
- No experimental rescue assay data available
Still missing
- No variant-specific experimental functional studies identified
Sources
PS4 No case-control studies have been reported for this variant. PS4 requires a statistically significant enrichment in affected individuals versus controls (p≤0.05, OR≥2 or lower 95% CI≥1.5). Details ▾Hide ▴
Evidence considered
- No case-control data available for this variant
Still missing
- No case-control studies identified
Sources
PP1 No co-segregation data is available for this variant. PP1 under the VCEP applies to autosomal recessive (A-T) conditions with segregation in affected relatives, but no family studies have been identified. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation data identified
Sources
PP3 REVEL score is not available for this indel variant (REVEL only scores single-nucleotide missense changes). SpliceAI max delta score is 0.01, well below the VCEP PP3 threshold of ≥0.2 for splicing prediction. Neither the missense (REVEL >0.733) nor the splicing (SpliceAI ≥0.2) rule for PP3 is met. Details ▾Hide ▴
Evidence considered
- REVEL not available for indel variant
- SpliceAI max delta 0.01 (threshold for PP3 is ≥0.2)
Sources
BA1 This variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires a Grpmax Filtering AF >0.5%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- Frequency 0 does not exceed BA1 threshold of >0.5%
Sources
BS1 This variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires a Grpmax Filtering AF >0.05%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- Frequency 0 does not exceed BS1 threshold of >0.05%
Sources
BS3 No experimental functional studies demonstrating rescue of ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity have been identified for this variant. The VCEP Suppl_TableS1 DeepATM computational prediction for the same amino acid change D1371N (via c.4111G>A) classifies it as 'Functional' but this is a predictive score, not experimental evidence meeting BS3 requirements. Details ▾Hide ▴
Evidence considered
- No experimental rescue assay data available
- DeepATM prediction for D1371N via c.4111G>A classified as 'Functional' (computational only)
Still missing
- No variant-specific experimental functional studies identified
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP2 No data on unaffected individuals carrying this variant in trans with a known pathogenic ATM variant or in homozygous state are available. BP2 requires observation of the variant in an unaffected individual aged ≥18 years with no evidence of A-T, in trans with a pathogenic/likely pathogenic ATM variant. Details ▾Hide ▴
Evidence considered
- No proband data available
Still missing
- No unaffected proband data identified
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is an in-frame 2-bp deletion-insertion (c.4110_4111delinsAA) producing a missense change (p.Asp1371Asn), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 under the ATM VCEP v1.5 applies only to null variants. Details ▾Hide ▴
Evidence considered
- In-frame delins producing missense p.(Asp1371Asn)
- VCEP PVS1 definition requires null variant (nonsense
- frameshift
- canonical splice)
Sources
vcep_atm_pvs1_1_5cspec ↗
PS2 VCEPVCEP ATM v1.5: de novo occurrences have not yet been observed for ATM; PS2 is not applicable for autosomal dominant or autosomal recessive ATM-related disease. Details ▾Hide ▴
PM1 VCEPVCEP ATM v1.5: PM1 is not applicable. Benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined for ATM. Details ▾Hide ▴
PM4 N/AVCEP ATM v1.5: PM4 is applicable only for stop-loss variants. In-frame insertions or deletions smaller than a single exon are explicitly excluded. This variant is a 2-bp in-frame delins, not a stop-loss variant. Details ▾Hide ▴
Evidence considered
- VCEP rule: PM4 restricted to stop-loss variants only
- in-frame delins <1 exon excluded
Sources
PM5 N/AVCEP ATM v1.5: PM5_Supporting applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied. This is an in-frame missense variant (D1371N) and does not meet PM5 criteria. Details ▾Hide ▴
Evidence considered
- VCEP rule: PM5 applies to frameshifting/truncating variants only
- In-frame missense change (D1371N) not eligible
Sources
cspec ↗pm5_candidates
PM6 VCEPVCEP ATM v1.5: PM6 is not applicable for autosomal dominant or autosomal recessive ATM-related disease. Informative de novo occurrences have not yet been observed. Details ▾Hide ▴
PP2 VCEPVCEP ATM v1.5: PP2 is not applicable. ATM does not have a defined low rate of benign missense variation. Details ▾Hide ▴
PP4 VCEPVCEP ATM v1.5: PP4 is not applicable. For autosomal dominant breast cancer, genetic heterogeneity precludes use. For autosomal recessive A-T, phenotype evidence is built into the PM3/BP2 table. Details ▾Hide ▴
PP5 VCEPVCEP ATM v1.5: PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS2 VCEPVCEP ATM v1.5: BS2 is not applicable. ATM has incomplete penetrance, and healthy adults may carry pathogenic ATM variants without manifesting disease. Details ▾Hide ▴
BS4 VCEPVCEP ATM v1.5: BS4 is not applicable. For autosomal dominant conditions, co-segregation analysis in low-penetrance genes can lead to false-positive results. For autosomal recessive A-T, informative instances of lack of co-segregation are too rare to weight. Details ▾Hide ▴
BP1 VCEPVCEP ATM v1.5: BP1 is not applicable. Missense pathogenic variants are known for ATM, so a missense variant cannot be discounted on the basis that only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- VCEP rule: BP1 not applicable (missense pathogenic variants are known for ATM)
Sources
BP3 VCEPVCEP ATM v1.5: BP3 is not applicable. The original ACMG description is 'in-frame deletions/insertions in a repetitive region without a known function' but the VCEP does not apply this criterion for ATM. Details ▾Hide ▴
BP5 VCEPVCEP ATM v1.5: BP5 is not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance for co-occurring variants in the general population. Details ▾Hide ▴
BP6 VCEPVCEP ATM v1.5: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/AVCEP ATM v1.5: BP7 applies only to synonymous and deep intronic variants. This variant is a missense change (p.Asp1371Asn) arising from an in-frame delins and does not fall within the BP7 scope. Details ▾Hide ▴
Evidence considered
- VCEP rule: BP7 restricted to synonymous and deep intronic variants
- Missense change D1371N is not synonymous
Sources
PS5 N/APS5 is not part of the standard ACMG/AMP 2015 criteria framework and is not listed in the ATM VCEP v1.5 specifications. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.4110_4111delinsAA
- Protein (HGVS p.)
- NP_000042.3:p.(Asp1371Asn)
- GRCh38
- chr11:108288977 GG>AA
- GRCh37
- chr11:108159704 GG>AA
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
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
BP4 SupportingSpliceAI predicts no significant splice impact for this variant (max delta score 0.01 ≤ 0.1 threshold), meeting the VCEP BP4 splicing rule. REVEL score is not available for this indel variant, so the missense-specific BP4 rule cannot be assessed. The SpliceAI result confirms no cryptic splice alteration, which is a valid line of benign computational evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 ≤ BP4 splicing threshold of 0.1
- No predicted splice donor/acceptor gain or loss
Still missing
- REVEL score unavailable for indel — protein-level benign computational evidence not assessed
Sources
PP3 REVEL score is not available for this indel variant (REVEL only scores single-nucleotide missense changes). SpliceAI max delta score is 0.01, well below the VCEP PP3 threshold of ≥0.2 for splicing prediction. Neither the missense (REVEL >0.733) nor the splicing (SpliceAI ≥0.2) rule for PP3 is met. Details ▾Hide ▴
Evidence considered
- REVEL not available for indel variant
- SpliceAI max delta 0.01 (threshold for PP3 is ≥0.2)
Sources
BP7 N/AVCEP ATM v1.5: BP7 applies only to synonymous and deep intronic variants. This variant is a missense change (p.Asp1371Asn) arising from an in-frame delins and does not fall within the BP7 scope. Details ▾Hide ▴
Evidence considered
- VCEP rule: BP7 restricted to synonymous and deep intronic variants
- Missense change D1371N is not synonymous
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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/?term=NM_000051.3%3Ac.4110_4111delinsAA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108159704-GG-AA?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108288977-GG-AA?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108288977-GG-AA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.4110…
- OncoKB ↗www.oncokb.org/gene/ATM/D1371N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.4110_4111delinsAA
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.