Variant classification summary

NM_000051.4:c.9049C>T

ATM · NP_000042.3:p.(Leu3017=) · NM_000051.4

GRCh37: chr11:108236113 C>T · GRCh38: chr11:108365386 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu3017=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v4.1, an allele frequency of 0 at or below the 0.001% threshold.

2

BP4 (Supporting): SpliceAI maximum delta 0.023 is below the 0.1 benign splicing threshold.

3

BP7 (Supporting): synonymous change p.(Leu3017=), assigned supporting strength by the ATM VCEP synonymous-variant rule.

4

Overall: Likely Benign, per VCEP Rule19 combining two Benign-supporting criteria (BP4 and BP7).

Final determination: ATM VCEP v1.5 Rule19 classifies a variant as Likely Benign when at least two Benign.Supporting criteria are met; BP4_Supporting and BP7_Supporting meet that rule.

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	Not met	Not met: synonymous p.(Leu3017=) creates no premature stop codon, and SpliceAI max delta 0.023 predicts no splice impact.	cspec vcep_atm_pvs1_1_5 spliceai
PS1	N/A	Not applicable: the variant is synonymous rather than missense, and no splice event matching a known pathogenic reference variant is documented.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	Not applicable: the ATM VCEP specifies PS2 is not used for ATM disease, so no de novo evidence is assigned.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result (kinase activity or rescue) was available.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no variant-specific case-control data (p-value <=0.05, OR/HR/RR >=2) were available.	cspec PMID:18163131 PMID:24366376 PMID:31429903
PM1	N/A	Not applicable: the ATM VCEP has no domain-table residue list, and the variant is synonymous rather than missense.	cspec
PM2	Met	Met (supporting): absent from gnomAD v4.1, an allele frequency of 0 at or below the 0.001% threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband, second ATM variant, or phase information was available.	cspec vcep_atm_pm3_bp2_1_5
PM4	Not met	Not met: PM4 applies only to stop-loss variants, and this synonymous change does not alter the termination codon.	cspec
PM5	N/A	Not applicable: PM5 targets truncating variants upstream of p.Arg3047; this synonymous change creates no premature stop codon.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP explicitly lists PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no family segregation, affected-relative genotype, or phase data for this variant were available.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 as not applicable, and the variant is synonymous.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.023 falls below the 0.2 threshold required for PP3.	cspec spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP designates PP4 as not applicable.	cspec
PP5	N/A	Not applicable: the ATM VCEP designates PP5 as not applicable, and no expert-panel ClinVar submission exists.	cspec clinvar
BA1	Not met	Not met: BA1 requires gnomAD allele frequency above 0.5%; the variant is absent from gnomAD v4.1.	cspec gnomad_v4
BS1	Not met	Not met: BS1 requires gnomAD allele frequency above 0.05%; the variant is absent from gnomAD v4.1.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP marks BS2 as not applicable.	cspec
BS3	Not assessed	Not assessed: no variant-specific rescue assay result (ATM-specific function or radiosensitivity) was available.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable: the ATM VCEP specifies BS4 as not applicable for this disease context.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 as not applicable because missense pathogenic variants are known.	cspec
BP2	Not assessed	Not assessed: no unaffected biallelic individual, in-trans pathogenic variant, or phase information was available.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP designates BP3 as not applicable.	cspec
BP4	Met	Met (supporting): SpliceAI maximum delta 0.023 is below the 0.1 benign splicing threshold.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP designates BP5 as not applicable.	cspec
BP6	N/A	Not applicable: the ATM VCEP designates BP6 as not applicable, and no expert-panel ClinVar submission exists.	cspec clinvar
BP7	Met	Met (supporting): the ATM VCEP assigns BP7 at supporting strength to synonymous variants like this one.	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.