NM_000051.3:c.1348G>T

ATM · NP_000042.3:p.(Glu450Ter) · NM_000051.3

GRCh37: chr11:108121540 G>T · GRCh38: chr11:108250813 G>T

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Glu450Ter)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (Very Strong): nonsense change p.(Glu450Ter) predicted to trigger nonsense-mediated decay, upstream of critical ATM domains.

PM2 (Supporting): absent from gnomAD v4.1 and v2.1, meeting the 0.001% allele-frequency threshold.

PM5 (Supporting): premature termination codon at residue 450, upstream of the VCEP p.Arg3047 truncation threshold.

Pathogenic: matches ATM VCEP v1.5 Rule4 (one Very Strong plus two Supporting criteria).

Final determination: Rule4 of the ATM VCEP v1.5 framework (1 Pathogenic.Very Strong + >=2 Pathogenic.Supporting) is satisfied, yielding 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): nonsense change p.(Glu450Ter) at ~15% of the protein is predicted to trigger nonsense-mediated decay, upstream of critical ATM domains.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	N/A	Not applicable: this is a nonsense (stop-gain) variant, not a missense change, so there is no amino acid substitution to compare against a reference variant.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: the ATM VCEP does not use PS2, since de novo occurrences are not informative for autosomal recessive disease.	cspec
PS3	Not assessed	Not assessed: insufficient evidence - this variant was not confirmed to have been tested in any VCEP-approved functional assay (Mitui 2009, Barone 2009, Scott 2002).
PS4	Not assessed	Not assessed: no case-control enrichment data (odds ratio, confidence interval, or p-value) for this variant was available.	cspec
PM1	N/A	Not applicable: the ATM VCEP explicitly marks PM1 (mutational hotspot) as not applicable for this gene.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1 and v2.1, meeting the VCEP's 0.001% allele-frequency threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband or in-trans evidence with a pathogenic ATM variant was available.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: PM4 applies only to stop-loss variants, and this is a stop-gain (nonsense) change.	cspec
PM5	Met	Met (Supporting): premature termination codon at residue 450 lies upstream of the VCEP's p.Arg3047 truncating-variant threshold.	cspec
PM6	N/A	Not applicable: the ATM VCEP marks PM6 as not applicable, and no de novo occurrence is documented.	cspec
PP1	Not assessed	Not assessed: no affected relatives or segregation data were available to support co-segregation.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 as not applicable, and this is not a missense variant.	cspec
PP3	N/A	Not applicable: the VCEP's SpliceAI-based PP3 excludes nonsense variants, which also cannot be combined with PVS1.	cspec spliceai
PP4	N/A	Not applicable: the ATM VCEP specification marks PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the ATM VCEP marks PP5 as not applicable, and the ClinVar record is a single laboratory submission.	cspec clinvar
BA1	Not met	Not met: absent from gnomAD v4.1, below the >0.5% BA1 allele-frequency threshold.	cspec gnomad_v4
BS1	Not met	Not met: absent from gnomAD v4.1, below the >0.05% BS1 allele-frequency threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: ATM cancer predisposition has incomplete penetrance, so observation in healthy individuals cannot be used as BS2.	cspec
BS3	Not assessed	Not assessed: insufficient evidence - this variant was not confirmed to have been tested in any VCEP-approved functional assay.
BS4	N/A	Not applicable: the ATM VCEP marks BS4 as not applicable for autosomal recessive ataxia-telangiectasia.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 as not applicable, and this variant is itself truncating, not missense.	cspec
BP2	Not assessed	Not assessed: no unaffected-carrier, trans-phase, or co-occurrence observations were available.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable for all ATM variants.	cspec
BP4	N/A	Not applicable: the SpliceAI-based BP4 sub-path excludes nonsense variants, and no calibrated missense predictor applies.	cspec spliceai bayesdel
BP5	N/A	Not applicable: the ATM VCEP marks BP5 as not applicable, and no separate disease-causing variant is documented.	cspec
BP6	N/A	Not applicable: the ATM VCEP marks BP6 as not applicable, and the ClinVar record is a single laboratory Likely pathogenic submission.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or deep intronic variants, and this is a coding nonsense change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.