Classification rationale

PM5PM2PVS1 Pathogenic

ATM c.4300A>T

The ATM c.4300A>T (p.Lys1434Ter; p.K1434*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the ATM VCEP PM2_Supporting threshold of 0.001% and well below the BS1 (>0.05%) and BA1 (>0.5%) thresholds.² This is a nonsense variant predicted to introduce a premature stop codon at Lys1434; SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting interpretation as a truncating loss-of-function event rather than a splice-altering event.³

PM5 + PM2 + PVS1 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗pvs1_variant_assessmentvcep_atm_pvs1_1_5cspec ↗

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 nonsense change predicted to introduce a premature stop codon at Lys1434. The ATM VCEP framework recognizes loss of function as an established disease mechanism for ATM and states that ATM exons in the reference transcript are constitutive without major rescue isoforms, supporting application of PVS1 for this truncating variant.

Variant bucket: nonsenseATM loss of function eligible for PVS1ATM VCEP PVS1 decision tree applies to truncating variants

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its population frequency is therefore below the ATM PM2_Supporting threshold of 0.001%, so PM2_Supporting is met.

gnomAD v4.1 absentgnomAD v2.1 absentATM PM2 threshold ≤0.001%

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

PM5 supporting Pathogenic

This nonsense variant introduces a premature stop at Lys1434, which is upstream of the ATM VCEP truncation cutoff at p.Arg3047Ter; under the ATM gene-specific rule, truncating variants with premature termination codons upstream of p.Arg3047Ter meet PM5_Supporting.

ATM PM5 uses a truncation-cutoff rule rather than classic same-residue PM5.Variant protein consequence p.(Lys1434Ter)/p.(K1434*) is upstream of p.Arg3047Ter.

cspec ↗

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

Pathogenic

PS3 No well-established functional study was identified showing that this specific variant impairs ATM-specific functional rescue, so PS3 cannot be assessed.

PS4 No case-control study or other evidence showing a statistically increased prevalence of this variant in affected individuals was identified, so PS4 cannot be assessed.

PM3 No proband data were identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 cannot be assessed.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the ATM PP3 splicing threshold of 0.2.

Benign

BA1 This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% filtering allele frequency.

BS1 This variant is absent from gnomAD v4.1, which is below the ATM BS1 threshold of greater than 0.05% filtering allele frequency.

BS3 No well-established functional study was identified showing normal ATM function or rescue for this specific variant, so BS3 cannot be assessed.

BP2 No co-occurrence data were identified showing this variant in trans or in cis with another pathogenic or likely pathogenic ATM variant, so BP2 cannot be assessed.

BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.03, which is below the ATM BP4 splicing threshold of 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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). BayesDel score = 0.634849.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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