Variant classification summary

NM_000051.4:c.2638+11A>G

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108138080 A>G · GRCh38: chr11:108267353 A>G

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.?

gnomAD AF

4.340240102082447e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 grpmax filtering AF 7.39e-06, below the 0.001% threshold.

2

BP4 (Supporting): SpliceAI maximum delta score 0.00, at or below the <=0.1 no-splice-impact threshold.

3

BP7 (Supporting): the variant sits 11 nucleotides into intron 17, beyond the +7 donor-site threshold.

4

Likely Benign: two Benign.Supporting codes (BP4 and BP7) satisfy ATM v1.5 Rule19, and PM2_Supporting is not treated as conflicting evidence.

Final determination: ClinGen HBOP ATM VCEP v1.5 criteria-combination Rule19: >= 2 Benign.Supporting criteria (BP4_Supporting + BP7_Supporting) is satisfied, so the variant is classified as Likely Benign.

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	N/A	Not applicable: an intronic +11 change outside the canonical +/-1,2 donor sites, with no null effect predicted.	cspec vcep_atm_pvs1_1_5 pvs1_generic_framework spliceai PMID:25741868
PS1	Not met	Not met: no pathogenic or likely pathogenic ATM variant is reported at the same nucleotide or donor motif.	cspec vcep_atm_ps1_1_5 spliceai clinvar
PS2	N/A	Not applicable: de novo occurrences are not informative for ATM, and no parental testing was available.	cspec PMID:25741868
PS3	Not assessed	Not assessed: no variant-specific functional assay exists, and the intronic change cannot be tested by the approved protein-rescue assays.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 spliceai PMID:25741868
PS4	Not met	Not met: no case-control study reports this variant, which is present in only 7 of 1,612,814 gnomAD alleles.	cspec clinvar gnomad_v4 gnomad_v2 PMID:25394175 PMID:24418350 PMID:25741868 PMID:20301317 PMID:20301790 PMID:20050888 PMID:28492532
PM1	N/A	Not applicable: ATM has no approved critical-domain table, and pathogenic and benign variants occur within the same domains.	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 grpmax filtering AF 7.39e-06, below the 0.001% threshold. Flagged for human review: the rule specifies gnomAD v4 frequency without stating whether grpmax or a single-population estimate applies.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected proband carries this variant, so the recessive case-point total is 0.0 against the 1.0-point threshold.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4 gnomad_v2 clinvar
PM4	N/A	Not applicable: the variant is intronic and causes no protein length change, which the criterion requires.	cspec PMID:25741868
PM5	Not met	Not met: the variant is deep intronic with no predicted splice impact and introduces no premature termination codon.	cspec pm5_candidates spliceai vcep_atm_pvs1_1_5
PM6	N/A	Not applicable: assumed de novo occurrences are not informative for ATM, and none was observed.	cspec
PP1	Not assessed	Not assessed: no pedigree, affected relative, or countable meiosis was available for segregation analysis.	cspec clinvar
PP2	N/A	Not applicable: ATM has no defined low rate of benign missense variation, and this variant is not missense.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score 0.00, well below the >=0.2 PP3 threshold.	cspec spliceai
PP4	N/A	Not applicable: phenotype specificity is already built into the ATM PM3/BP2 table rather than scored separately.	cspec
PP5	Not met	Not met: ClinVar contains zero expert-panel submissions, and all three laboratory submissions classify the variant Likely benign.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax filtering AF 0.000739%, roughly 676-fold below the 0.5% BA1 ceiling.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: grpmax filtering AF 0.000739%, about 68-fold below the 0.05% BS1 ceiling.	cspec gnomad_v4 gnomad_v2
BS2	N/A	Not applicable: the ATM specification disables BS2, and population data are covered under BA1, BS1, and PM2.	cspec
BS3	Not assessed	Not assessed: no variant-specific functional result exists, and the approved protein-rescue assays cannot assess an intronic change.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 spliceai PMID:25741868
BS4	N/A	Not applicable: lack of co-segregation in A-T families is too rare to carry weight and is instead routed to BP2.	cspec
BP1	N/A	Not applicable: missense pathogenic variants are known for ATM, and this variant is intronic rather than missense.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrier was reported, giving 0.0 points against the -1.0 threshold.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4 gnomad_v2 spliceai clinvar
BP3	N/A	Not applicable: the ATM specification disables BP3, and no in-frame deletion or insertion is present.	cspec
BP4	Met	Met (Supporting): SpliceAI maximum delta score 0.00, at or below the <=0.1 no-splice-impact threshold.	cspec spliceai
BP5	N/A	Not applicable: ATM's low penetrance makes co-occurring pathogenic variants too common to be informative.	cspec
BP6	Not met	Not met: ClinVar contains zero expert-panel submissions, and the aggregate Likely benign label comes only from single laboratories.	cspec clinvar
BP7	Met	Met (Supporting): the variant lies 11 nucleotides into intron 17, beyond the +7 donor-site deep-intronic threshold.	cspec spliceai

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