Classification rationale

PVS1PM2PM5 Pathogenic

ATM c.8315del

The ATM c.8315del (p.Gly2772GlufsTer34) variant has been reported in ClinVar with pathogenic and likely pathogenic clinical submissions.¹ This variant is absent from gnomAD v4.1 and gnomAD v2.1, supporting rarity in the general population.² ATM-specific criteria support pathogenic evidence for this truncating variant because p.(Gly2772GlufsTer34) introduces a premature termination codon upstream of the p.Arg3047 threshold used for ATM truncating variants, and ATM loss of function is an established disease mechanism.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.14.⁴

PVS1 + PM2 + PM5 → Pathogenic

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_a_t_m___p_v_s_1___1___5

4 spliceai ↗

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 · 3 applied · 10 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 · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

This variant is a frameshift deletion, NM_000051.4:c.8315del, predicted to cause p.(Gly2772GlufsTer34). ATM-specific guidance permits PVS1 for loss-of-function variants, and this variant is not in a context that would withhold PVS1 under the available ATM loss-of-function framework.

Frameshift consequence p.(Gly2772GlufsTer34)ATM loss of function is an established disease mechanismATM PVS1 guidance is applicable

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is 0%, which is below the ATM PM2_Supporting threshold of less than or equal to 0.001% in gnomAD v4.

Absent from gnomAD v4.1Absent from gnomAD v2.1

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

PM5 supporting Pathogenic

ATM-specific guidance allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Arg3047. This variant causes p.(Gly2772GlufsTer34), which truncates the protein upstream of p.Arg3047 and therefore meets that ATM-specific positional rule.

Predicted truncation at codon 2772 with premature termination 34 residues downstreamATM truncating-variant rule uses p.Arg3047 as the C-terminal threshold

cspec ↗

Assessed · not applied · 4 not met · 6 not assessed

Pathogenic

PS3 ATM-specific functional criteria require a validated assay showing failure to rescue ATM-specific function, with or without radiosensitivity depending on strength.

PS4 This variant has been reported in ClinVar, but no case-control study data were identified showing a p-value less than or equal to 0.05 together with an odds ratio, hazard ratio, or relative risk of at least 2, or a lower 95% confidence interval of at least 1.5.

PM3 ATM-specific PM3 requires qualifying observations in trans with a pathogenic or likely pathogenic ATM variant, scored under the ATM PM3/BP2 point framework.

PP1 ATM-specific PP1 requires segregation data in affected relatives for the recessive condition framework.

PP3 SpliceAI predicts a maximum delta score of 0.14.

Benign

BA1 This variant is absent from gnomAD v4.1.

BS1 This variant is absent from gnomAD v4.1.

BS3 ATM-specific functional criteria require a validated rescue assay showing rescue of ATM-specific function and/or radiosensitivity.

BP2 ATM-specific BP2 requires documented co-occurrence in trans or homozygosity in an unaffected person under the ATM PM3/BP2 point framework.

BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.14, but this value is above the ATM BP4 splicing threshold of less than or equal to 0.1.

N/A · 15 PS1 · 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

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53726306, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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