Variant classification summary

NM_000051.4:c.5692C>T

ATM · NP_000042.3:p.(Arg1898Ter) · NM_000051.4

GRCh37: chr11:108178641 C>T · GRCh38: chr11:108307914 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM3 strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg1898Ter)

gnomAD AF

3.718573406498331e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense change p.Arg1898Ter in exon 38 of 63 predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): essentially absent from population databases — gnomAD v4.1 AF 3.72e-06, well below the 0.001% rarity threshold.

3

PM3 (Strong): two unrelated ataxia-telangiectasia probands carry the variant in trans with other null alleles (6.0 points).

4

PM5 (Supporting): truncation at p.Arg1898Ter lies upstream of the VCEP's p.Arg3047 boundary.

5

PP5 (Supporting): ClinGen HBOP expert panel classified this exact variant as Pathogenic.

6

Synthesis: PVS1 very strong plus PM3 strong satisfies the VCEP Pathogenic rule; final classification: Pathogenic.

Final determination: Rule1 of the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework (1 Pathogenic.Very Strong + >=1 Pathogenic.Strong -> Pathogenic) is satisfied by PVS1 very strong plus PM3 strong, and Rule4 (1 Very Strong + >=2 Supporting -> Pathogenic) is independently satisfied by PVS1 plus PM2/PM5/PP5 supporting, so the final call is 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	Met: the nonsense change c.5692C>T creates a premature stop (p.Arg1898Ter) in exon 38 of 63, predicted to trigger nonsense-mediated decay.	cspec vcep_atm_pvs1_1_5 pvs1_generic_framework pvs1_gene_context PMID:25077176 PMID:17124347
PS1	N/A	Not applicable: PS1 requires a missense change matching a known pathogenic variant; c.5692C>T is a nonsense change.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP bars de novo evidence for this gene, and no de novo occurrence of this variant is reported.	cspec
PS3	Not assessed	Not assessed: no VCEP-approved functional assay result exists for this variant; the only functional-screen entry was a computational prediction.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:17124347 PMID:25077176
PS4	Not met	Not met: no case-control study of this variant exists; only individual ataxia-telangiectasia case reports, which cannot meet the VCEP's statistical threshold.	cspec PMID:17124347 PMID:25077176 PMID:21665257 PMID:23807571
PM1	N/A	Not applicable: the ATM VCEP marks PM1 inapplicable, and this nonsense variant has no missense domain argument.	cspec
PM2	Met	Met: the allele is essentially absent from population databases (gnomAD v4.1 AF 3.72e-06, 6/1,613,522 alleles), below the 0.001% rarity threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Met	Met: two unrelated ataxia-telangiectasia probands carry this allele in trans with other null variants (6.0 points on the VCEP table, strong).	cspec vcep_atm_pm3_bp2_1_5 PMID:17124347 PMID:25077176 gnomad_v4
PM4	N/A	Not applicable: PM4 applies only to stop-loss variants; c.5692C>T is a stop-gain (nonsense) change.	cspec
PM5	Met	Met: the truncation at p.Arg1898Ter lies upstream of the VCEP's p.Arg3047 boundary, meeting the gene-specific PM5 rule.	cspec PMID:17124347 PMID:25077176
PM6	N/A	Not applicable: the ATM VCEP bars de novo evidence for ATM, and no assumed de novo occurrence is reported.	cspec
PP1	Not met	Not met: no affected relative carrying this variant is reported, so no segregation evidence exists.	cspec PMID:17124347 PMID:25077176
PP2	N/A	Not applicable: the ATM VCEP marks PP2 inapplicable, and missense-predominance reasoning does not apply to a nonsense change.	cspec
PP3	N/A	Not applicable: the VCEP's PP3 sub-paths (REVEL, SpliceAI >= 0.2) do not cover nonsense variants; SpliceAI max delta is 0.081.	cspec spliceai bayesdel vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP explicitly declares PP4 inapplicable; phenotype specificity is not scored separately.	cspec
PP5	Met	Met: the ClinGen HBOP expert panel (3-star) classified this exact variant as Pathogenic.	clinvar cspec
BA1	Not met	Not met: grpmax filtering allele frequency is 6.8e-07 (0.000068%), about four orders of magnitude below the 0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: grpmax filtering allele frequency 6.8e-07 (0.000068%) is nearly three orders of magnitude below the 0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 inapplicable for this gene.	cspec
BS3	Not assessed	Not assessed: no VCEP-approved assay result showing preserved ATM function or normal radiosensitivity is available.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:17124347 PMID:25077176
BS4	N/A	Not applicable: the ATM VCEP does not weight lack-of-segregation evidence, and no unaffected carriers are reported.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 inapplicable, and this is a truncating rather than missense change.	cspec
BP2	Not met	Not met: no unaffected individual carrying this variant with a pathogenic variant in trans was identified (0 points).	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
BP3	N/A	Not applicable: the ATM VCEP marks BP3 inapplicable, and this is a nonsense substitution, not an in-frame indel.	cspec
BP4	N/A	Not applicable: a clean SpliceAI score (max delta 0.081) only rules out a splicing effect; the protein-truncating, NMD-triggering effect remains.	cspec spliceai bayesdel vcep_suppl_tables1_pmid_40580951 PMID:25077176
BP5	N/A	Not applicable: the ATM VCEP explicitly declares BP5 inapplicable for ATM.	cspec
BP6	Not met	Not met: no expert-panel benign classification exists; the only expert-panel call for this variant is Pathogenic.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies only to synonymous and deep intronic variants; c.5692C>T is an exonic nonsense change.	cspec spliceai

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