Variant classification summary

NM_000051.4:c.1039G>T

ATM · NP_000042.3:p.(Glu347Ter) · NM_000051.4

GRCh37: chr11:108117828 G>T · GRCh38: chr11:108247101 G>T

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.(Glu347Ter)

gnomAD AF

1.858980237800752e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense variant p.(Glu347Ter) predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): gnomAD v4 allele frequency 0.000186% is below the 0.001% rarity threshold.

3

PM5 (Supporting): premature termination codon p.(Glu347Ter) lies upstream of p.Arg3047 per the ATM VCEP truncating-variant rule.

4

Overall classification: Pathogenic by ATM VCEP Rule 4 (PVS1 very strong plus PM2 and PM5 supporting).

Final determination: ATM VCEP v1.5 Rule4 classifies a variant as Pathogenic when one Pathogenic Very Strong criterion and at least two Pathogenic Supporting criteria are met.

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: c.1039G>T creates a premature stop at residue 347 of the 3057-residue ATM protein, upstream of the final coding exon and predicted to trigger nonsense-mediated decay.	cspec vcep_atm_pvs1_1_5
PS1	N/A	Not applicable: this nonsense change (p.Glu347Ter) is outside the PS1 missense and splice-region pathways.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 because informative de novo occurrences have not been observed.	cspec
PS3	Not assessed	Not assessed: Sun et al. 2025 shows loss of function, but this assay is not among the three ATM VCEP-calibrated assays, so PS3 awaits expert review.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no qualifying case-control study was available for this variant.	cspec
PM1	N/A	Not applicable: PM1 addresses missense variants in critical domains; this is a nonsense change.	cspec
PM2	Met	Met: gnomAD v4 aggregate allele frequency 0.000186% is below the PM2 Supporting cutoff of 0.001%. Flagged for human review: the Admixed American subpopulation frequency (0.005%) exceeds the cutoff.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected ataxia-telangiectasia proband, second ATM variant, or phase information was available.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants; c.1039G>T is a nonsense change creating p.(Glu347Ter).	cspec
PM5	Met	Met: the premature stop p.(Glu347Ter) lies upstream of p.Arg3047, meeting the ATM VCEP PM5 supporting rule for truncating variants.	cspec
PM6	N/A	Not applicable: the ATM VCEP excludes PM6 because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: no pedigree or segregation data were available to demonstrate the variant co-segregates with disease.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 not applicable, and this is a nonsense, not missense, variant.	cspec
PP3	N/A	Not applicable: PP3 splice-prediction scope covers silent, missense/in-frame, and non-canonical intronic variants, not exonic nonsense changes.	cspec spliceai
PP4	N/A	Not applicable: the ATM VCEP forbids PP4 for both ATM-associated cancer predisposition and ataxia-telangiectasia.	cspec
PP5	N/A	Not applicable: the ATM VCEP excludes PP5, and no ClinVar expert-panel pathogenic assertion exists for this exact variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v4 grpmax filtering allele frequency 0.001327% is far below the 0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4 grpmax filtering allele frequency 0.001327% is below the 0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP designates BS2 as not applicable.	cspec
BS3	Not assessed	Not assessed: available functional data show loss of function rather than rescue, so no variant-specific normal-function result supported BS3.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: the ATM VCEP specifies BS4 as not applicable for both ATM-associated conditions.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 not applicable, and this is a nonsense, not missense, variant.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrying the variant with a pathogenic ATM variant in trans, and no cis co-occurrence observation, was available.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP forbids BP3, and this is a single-nucleotide nonsense change, not an in-frame indel.	cspec
BP4	Not met	Not met: SpliceAI maximum delta score 0.307 exceeds the ≤0.1 BP4 threshold.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP specifies that BP5 must not be used.	cspec
BP6	N/A	Not applicable: the ATM VCEP excludes BP6, and no ClinVar expert-panel benign assertion exists for this exact variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 is limited to synonymous and qualifying deep-intronic variants; this is an exonic nonsense change.	cspec

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