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%.1 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.2 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 BS3.3 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.4
ATM
Final classification
Uncertain Significance - Conflicting Evidence
ATM c.4110_4111delinsAA · p.Asp1371Asn
ATM
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%.
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.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
ATM c.4110_4111delinsAA
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
3
vcep_suppl_tables1_pmid_40580951clinvar ↗
4
final_classification_framework
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 9 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
BP4
supporting
Benign
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.
SpliceAI max delta 0.01 ≤ BP4 splicing threshold of 0.1No predicted splice donor/acceptor gain or loss
Assessed · not applied
Pathogenic
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.
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.
PS4
No case-control studies have been reported for this variant.
PP1
No co-segregation data is available for this variant.
PP3
REVEL score is not available for this indel variant (REVEL only scores single-nucleotide missense changes).
Benign
BA1
This variant is absent from gnomAD v4.1.
BS1
This variant is absent from gnomAD v4.1.
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.
BP2
No data on unaffected individuals carrying this variant in trans with a known pathogenic ATM variant or in homozygous state are available.
N/A · 16
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links