Variant classification summary

NM_000051.4:c.5574G>A

ATM · NP_000042.3:p.(Trp1858Ter) · NM_000051.4

GRCh37: chr11:108175479 G>A · GRCh38: chr11:108304752 G>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM3 moderate PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Trp1858Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): stop-gain p.Trp1858Ter is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.

2

PM3 (Moderate): one unrelated A-T proband (AT35RM) with a confident phenotype carries the variant with a second truncating ATM allele, phase unknown (2.0 points).

3

PM2 (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold.

4

PM5 (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047.

5

Overall: Pathogenic under the ClinGen HBOP ATM VCEP v1.5, from PVS1 (very strong) plus PM2 and PM5 (supporting) satisfying Rule 4 (≥1 very strong + ≥2 supporting), with PM3 (moderate) as additional support.

Final determination: Rule4 of the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework (==1 Pathogenic.Very Strong plus >=2 Pathogenic.Supporting) is satisfied by PVS1 very strong with PM2 supporting and PM5 supporting, classifying the variant 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	Met (Very Strong): stop-gain at residue 1858 is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: this is a nonsense change, and PS1 applies only to missense or splice-region variants.	cspec vcep_atm_ps1_1_5 spliceai clinvar
PS2	N/A	Not applicable: the ATM VCEP does not apply de novo criteria, and no trio or parental testing data exists for this variant.	cspec
PS3	Not assessed	Not assessed: no direct functional assay evidence was available; the sole functional-screen entry is a computational prediction, which the VCEP excludes.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:10864201 PMID:12105990 PMID:23807571 PMID:25614872
PS4	Not met	Not met: no case-control study of this variant exists; only case observations without a p-value or odds ratio are documented.	PMID:10864201 PMID:12105990 clinvar cspec
PM1	N/A	Not applicable: the ATM VCEP declares PM1 not applicable, and the variant is a stop-gain, not a missense substitution.	cspec vcep_atm_pvs1_1_5
PM2	Met	Met (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Met	Met (Moderate): one unrelated A-T proband (AT35RM) with a confident phenotype carries the variant with a second truncating ATM allele, phase unknown (2.0 points).	PMID:10864201 PMID:12105990 vcep_atm_pm3_bp2_1_5 gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	Not applicable: PM4 is for stop-loss variants; this is a stop-gain (nonsense) change.	cspec
PM5	Met	Met (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047.	cspec clinvar PMID:12105990 PMID:10864201
PM6	N/A	Not applicable: the ATM VCEP marks PM6 not applicable, and no unconfirmed-de-novo or parental testing data exists.	cspec
PP1	Not assessed	Not assessed: no segregation data exists; no affected relative, parental, or meiosis testing is reported for this variant.	PMID:10864201 PMID:12105990 PMID:23807571 PMID:25614872 cspec
PP2	N/A	Not applicable: the ATM VCEP declares PP2 not applicable, and the variant is a truncating change, not missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.01 is well below the 0.2 splicing threshold, and the missense sub-path does not apply to a nonsense variant.	spliceai cspec bayesdel vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP routes phenotype evidence through the PM3/BP2 points system and marks PP4 not applicable.	cspec vcep_atm_pm3_bp2_1_5
PP5	N/A	Not applicable: the ClinVar record is a 1-star single-laboratory submission, not an expert-panel classification, so PP5 cannot be applied.	clinvar cspec
BA1	Not met	Not met: allele frequency 0 (absent from gnomAD v4.1) is far below the >0.5% BA1 threshold.	gnomad_v4 cspec
BS1	Not met	Not met: allele frequency 0 (absent from gnomAD v4.1) is below the >0.05% BS1 threshold.	gnomad_v4 cspec
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 not applicable for ATM.	cspec
BS3	Not assessed	Not assessed: no calibrated assay evidence that the variant preserves ATM function was available.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:10864201 PMID:12105990 PMID:23807571 PMID:25614872
BS4	N/A	Not applicable: the ATM VCEP marks BS4 not applicable, and no family non-segregation data exists.	cspec
BP1	N/A	Not applicable: the ATM VCEP declares BP1 not applicable, and the variant is a truncating change, not missense.	cspec
BP2	Not met	Not met: no unaffected adult carrier of the variant with a second P/LP ATM allele is documented (0 BP2 points).	gnomad_v2 gnomad_v4 gnomad_canada clinvar vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable, and this is a nonsense substitution, not an in-frame repeat-region indel.	cspec
BP4	N/A	Not applicable: per the lab override, the BP4 splicing sub-path (SpliceAI ≤0.1) is not applied to nonsense variants whose mechanism is protein truncation.	cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP marks BP5 not applicable, and no alternate molecular basis of disease is documented.	cspec
BP6	N/A	Not applicable: the ClinVar record is a 1-star single-laboratory Pathogenic submission, not a benign expert-panel classification, so BP6 cannot be applied.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies to synonymous and deep intronic variants; this is an exonic nonsense change.	cspec

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