Classification rationale

PVS1PM5 Likely Pathogenic

ATM c.8395_8404del

ATM HBOP VCEP v1.5 supports PVS1 for null variants through the ATM PVS1 decision tree, and this variant is an exonic frameshift with predicted consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4).¹ ATM-specific PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047; this variant truncates at codon 2802, upstream of that boundary.² PM2 was not applied because gnomAD v4 shows 20/1613922 alleles (0.00124%), slightly above the ATM PM2_Supporting threshold of 0.001%.³ ClinVar contains a concordant ClinGen HBOP expert-panel Pathogenic classification for this variant, but that assertion was treated as contextual support rather than as a standalone ACMG criterion.⁴

PVS1 + PM5 → Likely Pathogenic

1 cspec ↗

2 cspec ↗

3 gnomad_v4 ↗

4 clinvar ↗

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.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 12 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 Very Strong Pathogenic

ATM HBOP VCEP v1.5 allows PVS1 via the ATM decision tree for null variants. NM_000051.4:c.8395_8404del is an exonic frameshift with predicted protein consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4); the event is upstream of the ATM truncation boundary referenced in the specification and there is no evidence from SpliceAI of an alternate splice mechanism that would replace the expected loss-of-function interpretation.

Frameshift in ATMPredicted protein: p.(Phe2799LysfsTer4)SpliceAI max delta 0.07

cspec ↗spliceai ↗

PM5 Supporting Pathogenic

ATM HBOP VCEP specifies PM5_Supporting for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a stop at codon 2802, which is upstream of p.Arg3047.

Protein consequence p.(Phe2799LysfsTer4) terminates before p.Arg3047

cspec ↗

Assessed · not applied · 3 not met · 9 not assessed

Pathogenic

PS1 No same-amino-acid or same-splicing-event reference variant evidence was extracted in the workspace for PS1 assessment.

PS3 The workspace contains ATM functional-framework materials, but no curated variant-specific rescue/failure-to-rescue data for c.8395_8404del were extracted for direct PS3 use.

PS4 The workspace did not provide a case-control analysis satisfying the ATM PS4 rule.

PM2 ATM PM2 is downgraded to PM2_Supporting and requires frequency <=0.001% in gnomAD v4.

PM3 ATM PM3 requires proband-level recessive evidence with phase/zygosity scoring.

PP1 No family segregation data were extracted for affected relatives with biallelic ATM variants, so PP1 was not applied.

PP3 PP3 is not applied.

Benign

BA1 The gnomAD v4 frequency is far below the ATM BA1 stand-alone threshold (>0.5%).

BS1 The gnomAD v4 frequency is far below the ATM BS1 threshold (>0.05%).

BS3 No variant-specific evidence showing rescue of ATM-specific function or radiosensitivity was extracted for this allele, so BS3 was not applied.

BP2 ATM BP2 also requires proband-level co-occurrence/phase information in unaffected individuals; no such evidence was extracted in the workspace.

BP4 SpliceAI shows no significant splice impact (max delta 0.07), but BP4 is not used here because the variant is an obvious frameshift loss-of-function allele and splice-only benign computational evidence does not address the primary predicted protein-damaging mechanism.

N/A · 14 PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

Allele frequency by ancestry

three datasets · side by side

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (23 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).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

Functional

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV53730617, n = 6 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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