Variant classification summary

NM_000051.4:c.4300A>T

ATM · NP_000042.3:p.(Lys1434Ter) · NM_000051.4

GRCh37: chr11:108160392 A>T · GRCh38: chr11:108289665 A>T

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PM5 supporting PM2 supporting PVS1 very strong

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Lys1434Ter)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
BP3	N/A	BP3 is not applicable because the ATM VCEP does not use this criterion for ATM variants.	cspec
BP2	Not assessed	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.	cspec vcep_atm_pm3_bp2_1_5
BA1	Not met	This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% filtering allele frequency.	gnomad_v4 cspec
PP4	N/A	PP4 is not applicable because the ATM VCEP does not use this criterion for ATM in either the dominant cancer-predisposition or recessive A-T context.	cspec
PM6	N/A	PM6 is not applicable because the ATM VCEP does not use de novo evidence for ATM variant interpretation in this framework.	cspec
PS4	Not assessed	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.	clinvar cspec
BP6	N/A	BP6 is not applicable because this criterion is not used by the ATM VCEP.	cspec
PM5	Met	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.	cspec pm5_candidates
PM1	N/A	PM1 is not applicable because the ATM VCEP does not use hotspot or critical-domain PM1 for ATM.	cspec
PS2	N/A	PS2 is not applicable because the ATM VCEP does not use de novo evidence for ATM in this framework.	cspec
PS1	N/A	PS1 is not applicable because this variant is a nonsense change and no same-amino-acid or qualifying splice-event comparator evidence was identified under the ATM PS1 framework.	cspec vcep_atm_ps1_1_5
BP5	N/A	BP5 is not applicable because the ATM VCEP does not use this criterion for ATM.	cspec
PP3	Not met	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. A BayesDel score of 0.634849 is available, but the ATM VCEP PP3 rule is defined for missense REVEL evidence or for predicted splice-impact evidence and does not support PP3 for this truncating variant without predicted splice disruption.	spliceai bayesdel cspec
PP2	N/A	PP2 is not applicable because the ATM VCEP does not use PP2 for ATM.	cspec
PM3	Not assessed	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.	cspec vcep_atm_pm3_bp2_1_5
PM2	Met	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 gnomad_v2 cspec
PVS1	Met	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.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
BP7	N/A	BP7 is not applicable because this variant is not synonymous and not a deep intronic variant.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, which is below the ATM BS1 threshold of greater than 0.05% filtering allele frequency.	gnomad_v4 cspec
PM4	N/A	PM4 is not applicable because the ATM VCEP uses PM4 only for stop-loss variants, and this variant is a nonsense change.	cspec
BP4	Not met	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. However, BP4 is not met because this variant introduces a premature stop codon and therefore is not predicted to have no impact on the gene product; the available BayesDel score of 0.634849 is also not used by the ATM VCEP BP4 rule for this truncating variant.	spliceai bayesdel cspec
BP1	N/A	BP1 is not applicable because the ATM VCEP does not use BP1 for ATM.	cspec
BS4	N/A	BS4 is not applicable because the ATM VCEP does not use lack of segregation evidence for ATM in this framework.	cspec
BS3	Not assessed	No well-established functional study was identified showing normal ATM function or rescue for this specific variant, so BS3 cannot be assessed.	cspec
BS2	N/A	BS2 is not applicable because the ATM VCEP does not use BS2 for ATM due to incomplete penetrance.	cspec
PP5	N/A	PP5 is not applicable because this criterion is not used by the ATM VCEP.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
PS3	Not assessed	No well-established functional study was identified showing that this specific variant impairs ATM-specific functional rescue, so PS3 cannot be assessed.	cspec

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