Variant classification summary

NM_000051.3:c.4158dup

ATM · NP_000042.3:p.(Lys1387Ter) · NM_000051.3

GRCh37: chr11:108159750 A>AT · GRCh38: chr11:108289023 A>AT

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PM5 supporting PM2 supporting PVS1 very strong BP4 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Lys1387Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.4158dup (p.Lys1387Ter, p.K1387*) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel.

2

This variant is absent from gnomAD v4.1 and gnomAD v2.1, which supports PM2_Supporting and does not meet the BA1 or BS1 population thresholds.

3

This variant introduces a premature stop at Lys1387 in ATM, and the ATM HBOP VCEP framework supports full-strength PVS1 for this truncating event; the same gene-specific framework also supports PM5_Supporting because the stop is upstream of the ATM truncation cutoff at p.Arg3047Ter.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which supports BP4 and does not support PP3 under the ATM VCEP splice thresholds.

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	ATM HBOP VCEP guidance states BP3 is not applicable for ATM.	cspec
BP2	Not assessed	No reviewed evidence showed this variant in cis or in an unaffected adult in trans or homozygous with another pathogenic or likely pathogenic ATM variant, so BP2 cannot be assigned from the available data.	cspec vcep_atm_pm3_bp2_1_5 PMID:23807571 PMID:25614872 PMID:26896183
BA1	Not met	This variant is absent from gnomAD v4.1, which is below the ATM BA1 threshold of greater than 0.5% group maximum filtering allele frequency.	gnomad_v4 cspec
PP4	N/A	ATM HBOP VCEP guidance states PP4 should not be used for ATM.	cspec
PM6	N/A	ATM HBOP VCEP guidance states PM6 should not be used for ATM.	cspec
PS4	Not assessed	The available evidence confirms ClinVar reporting, but no reviewed case-control dataset provided a p-value of 0.05 or less together with an odds ratio, hazard ratio, or relative risk meeting the ATM PS4 threshold, so PS4 was not assigned.	clinvar cspec PMID:23807571 PMID:25614872 PMID:26896183
BP6	N/A	ATM HBOP VCEP guidance states BP6 is not for use.	cspec
PM5	Met	This truncating variant introduces a premature stop at Lys1387, which is upstream of the ATM HBOP VCEP truncation cutoff at p.Arg3047Ter, so the ATM gene-specific PM5_Supporting rule is met.	cspec pm5_candidates
PM1	N/A	ATM HBOP VCEP guidance states PM1 should not be used for ATM because germline mutational hotspots are not well defined.	cspec
PS2	N/A	ATM HBOP VCEP guidance states PS2 should not be used for ATM.	cspec
PS1	N/A	ATM HBOP VCEP guidance limits PS1 use to missense changes and defined splicing scenarios, whereas this variant is truncating.	cspec vcep_atm_ps1_1_5
BP5	N/A	ATM HBOP VCEP guidance states BP5 should not be used for ATM.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM PP3 splice threshold of 0.2. REVEL and BayesDel are not applicable here because this is not a missense SNV.	spliceai cspec
PP2	N/A	ATM HBOP VCEP guidance states PP2 should not be used for ATM.	cspec
PM3	Not assessed	No reviewed patient-level evidence established this variant in trans with another pathogenic or likely pathogenic ATM variant with sufficient phenotype and phase detail to assign PM3 under the ATM point-based framework.	cspec vcep_atm_pm3_bp2_1_5 PMID:23807571 PMID:25614872 PMID:26896183
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1, which is below the ATM PM2_Supporting threshold of 0.001% in gnomAD v4.	gnomad_v4 gnomad_v2 cspec
PVS1	Met	This variant creates a premature termination at Lys1387 in the ATM reference transcript NM_000051.3, a transcript for which the ATM HBOP VCEP considers all exons constitutive. The stop occurs in exon 28 with 13 downstream exons remaining, and SpliceAI does not suggest an alternative splice-mediated rescue mechanism (max delta score 0.02), so full-strength PVS1 is supported under the ATM VCEP PVS1 framework.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment spliceai
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, whereas this variant is truncating.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, which is below the ATM BS1 threshold of greater than 0.05% group maximum filtering allele frequency.	gnomad_v4 cspec
PM4	N/A	ATM HBOP VCEP guidance limits PM4 to stop-loss variants, and this variant is truncating rather than stop-loss.	cspec
BP4	Met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.02, which is below the ATM BP4 splice threshold of 0.1. This supports the expected truncating interpretation rather than an alternative splice-mediated effect.	spliceai cspec
BP1	N/A	ATM HBOP VCEP guidance states BP1 should not be used for ATM.	cspec
BS4	N/A	ATM HBOP VCEP guidance states BS4 should not be used for ATM.	cspec
BS3	Not assessed	No reviewed variant-specific assay showed rescue of ATM-specific function or radiosensitivity for this variant, so BS3 was not assigned.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448
BS2	N/A	ATM HBOP VCEP guidance states BS2 should not be used for ATM because of incomplete penetrance.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
PP1	Not assessed	No reviewed segregation data documented this variant tracking with disease in affected relatives in a way that meets the ATM AR-specific PP1 framework, so PP1 was not assigned.	cspec PMID:23807571 PMID:25614872 PMID:26896183
PS3	Not assessed	No reviewed variant-specific assay showed failure to rescue ATM-specific function or radiosensitivity for this variant under the ATM VCEP functional framework, so PS3 was not assigned.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448

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