Variant classification summary

NM_000051.4:c.273dup

ATM · NP_000042.3:p.(Lys92GlufsTer8) · NM_000051.4

GRCh37: chr11:108099991 A>AG · GRCh38: chr11:108229264 A>AG

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Lys92GlufsTer8)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift duplication predicted to trigger nonsense-mediated decay; loss-of-function is an established ATM disease mechanism.

2

PM2 (Supporting): variant is absent from gnomAD v4.1 and other population databases, below the panel's 0.001% frequency threshold.

3

PM5 (Supporting): premature stop codon at residue 99 lies upstream of the most C-terminal known pathogenic residue (p.Arg3047), satisfying the panel's truncation rule.

4

Overall classification: Pathogenic, per ATM expert panel combination Rule 4 (PVS1 Very Strong plus two supporting criteria, PM2 and PM5).

Final determination: Rule4 of the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework (1 Pathogenic.Very Strong PVS1 + >=2 Pathogenic.Supporting criteria) is satisfied by PVS1 (very strong), PM2 (supporting), and PM5 (supporting), 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
PVS1	Met	PVS1 (Very Strong): This one-base duplication in exon 4 of ATM shifts the reading frame (p.Lys92GlufsTer8) and creates a premature stop codon at residue 99 of the 3,056-residue protein, which is predicted to trigger nonsense-mediated decay. Loss-of-function is an established disease mechanism for ATM, and the variant is absent from population databases (gnomAD v2.1, v4.1, and gnomAD-Canada).	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai gnomad_v2 gnomad_v4 gnomad_canada
PS1	N/A	PS1 does not apply: the ATM expert panel limits this criterion to missense changes producing the same amino-acid substitution as an established pathogenic variant, or to splice-region variants. This is a frameshift duplication with neither a comparable missense change nor a splice effect (no splice impact predicted).	cspec vcep_atm_ps1_1_5 pm5_candidates
PS2	N/A	PS2 does not apply: the ATM expert panel specifications declare this criterion not applicable, and no confirmed de novo occurrence of this variant has been reported.	cspec
PS3	Not assessed	PS3 was not assessed: insufficient evidence was available. The expert panel accepts functional evidence only from its specified ATM functional assays, and none of them reports this variant; although a damaging effect is mechanistically expected for a frameshift, the criterion requires variant-specific validated assay data.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 oncokb PMID:27413114 PMID:30348496 PMID:30553448
PS4	Not assessed	PS4 was not assessed: no case-control or cohort study reporting this exact variant was identified. The variant is absent from ClinVar, population databases, and COSMIC, and is not described in the relevant literature.	clinvar cspec PMID:27413114 PMID:30348496 PMID:30553448
PM1	N/A	PM1 does not apply: the ATM expert panel states that benign and pathogenic variants occur in the same domains and that germline mutational hotspots are not well defined for ATM, so the criterion is not used. It also targets missense variants, whereas this is a frameshift null variant.	cspec
PM2	Met	PM2 (Supporting): the variant is absent from gnomAD v4.1 exomes, and from gnomAD v2.1 and gnomAD-Canada, placing it well below the expert panel's 0.001% frequency threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Not met	PM3 is not met: no observations of this variant in individuals with ataxia-telangiectasia were identified in any source, so it accrues zero points on the expert panel's points-based scale, below the 1-point threshold for supporting evidence.	vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada PMID:27413114 PMID:30348496 PMID:30553448
PM4	N/A	PM4 does not apply: the ATM expert panel restricts this criterion to stop-loss variants only. This is a frameshift duplication, whose protein-truncating effect is already captured by PVS1.	cspec
PM5	Met	PM5 (Supporting): the frameshift produces a premature stop codon at residue 99, far upstream of the most C-terminal known pathogenic ATM residue (p.Arg3047), satisfying the expert panel's truncation-cutoff rule.	cspec pm5_candidates
PM6	N/A	PM6 does not apply: the ATM expert panel specifications declare this criterion not applicable, and no presumed de novo occurrence of this variant has been reported.	cspec
PP1	Not assessed	PP1 was not assessed: no segregation data for this variant is available. No affected relatives or family studies were reported, and the variant is absent from ClinVar and the published literature.	cspec
PP2	N/A	PP2 does not apply: the ATM expert panel notes that ATM does not have a low rate of missense benign variation, so the criterion is not used; it also targets missense variants rather than frameshift null variants.	cspec
PP3	Not met	PP3 is not met: this is a frameshift duplication rather than a missense or splice-altering variant, and its predicted splice impact (computational splice score 0.00) is far below the expert panel's 0.2 threshold.	spliceai cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	PP4 does not apply: the ATM expert panel specifications declare it not applicable, because phenotype specificity for ataxia-telangiectasia is already built into the PM3/BP2 points system.	cspec
PP5	N/A	PP5 does not apply: the ATM expert panel declares it not applicable, and the variant has no ClinVar record at all, so no expert-panel classification exists that could invoke it.	clinvar cspec
BA1	Not met	BA1 is not met: the variant is absent from gnomAD v4.1, far below the 0.5% allele-frequency threshold used to flag benign population variants.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS1	Not met	BS1 is not met: the variant is absent from gnomAD v4.1, far below the 0.05% threshold, and it does not occur at a frequency greater than expected for ATM-related disease in any population dataset.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS2	N/A	BS2 does not apply: the ATM expert panel notes that ATM has incomplete penetrance, so observations of the variant in unaffected individuals carry no benign weight under this specification.	cspec
BS3	Not assessed	BS3 was not assessed: insufficient evidence was available. No functional studies showing that this variant preserves ATM function were identified; the panel accepts only its specified functional assays, and none reports this variant.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 oncokb PMID:27413114 PMID:30348496 PMID:30553448
BS4	N/A	BS4 does not apply: the ATM expert panel specifications declare it not applicable, and no data on absence of the variant in affected family members is available.	cspec
BP1	N/A	BP1 does not apply: the ATM expert panel notes that missense pathogenic variants are known in ATM, so the criterion is not used; it also targets missense variants rather than frameshift null variants.	cspec
BP2	Not met	BP2 is not met: no unaffected carriers of this variant were identified in any source, so it accrues zero points, which does not meet the -1-point threshold for supporting benign evidence.	vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3	N/A	BP3 does not apply: the ATM expert panel instructs that this criterion not be used, and c.273dup is an out-of-frame frameshift duplication rather than an in-frame indel in a repetitive region.	cspec
BP4	Not met	BP4 is not met: a clean computational splice prediction (score 0.00) only rules out a splice effect; the variant's primary mechanism is protein truncation through the frameshift, and the expert panel's rules do not allow the splice result to offset that protein-level effect.	spliceai cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	BP5 does not apply: the ATM expert panel specifications declare it not applicable, and no evidence of an alternate genetic cause in carriers of this variant exists.	cspec
BP6	N/A	BP6 does not apply: the ATM expert panel declares it not applicable, and the variant has no ClinVar record, so no expert-panel benign classification exists that could invoke it.	clinvar cspec
BP7	N/A	BP7 does not apply: the criterion is defined for synonymous and deep intronic variants, whereas c.273dup is a coding frameshift duplication in exon 4.	cspec

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