Variant classification summary

NM_000051.4:c.3285-15C>T

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108150203 C>T · GRCh38: chr11:108279476 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

1.4835532002177598e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: BP4 (supporting) - SpliceAI maximum delta 0.01 meets the ATM VCEP <=0.1 threshold for no predicted splice impact.

Final determination: No ClinGen HBOP ATM VCEP Version 1.6 criteria-combination rule matches the adjudicated evidence because BP4 supporting is the only criterion met; therefore the variant remains a VUS.

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: intronic c.3285-15C>T is outside canonical +/-1,2 splice sites and SpliceAI max delta is 0.01, below the 0.2 splice-impact threshold.	cspec spliceai pvs1_gene_context
PS1	Not assessed	Not assessed: ATM PS1 requires a matched pathogenic splice reference, but no c.3285-15C>T or p.? entry was found and SpliceAI max delta is only 0.01.	vcep_atm_ps1_1_5 vcep_atm_ps1_1_6 cspec spliceai
PS2	N/A	Not applicable: the governing ATM VCEP version 1.6 explicitly designates PS2 as Not Applicable.	cspec
PS3	Not assessed	Not assessed: no variant-specific damaging assay result was found, and ATM VCEP PS3 requires an exact tested-variant result with calibrated ATM functional readouts.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no variant-specific case-control p-value, enrichment estimate, or confidence interval is available for comparison with the VCEP PS4 thresholds.	cspec PMID:15604628 PMID:25085752 PMID:25394175 PMID:34012068
PM1	N/A	Not applicable: c.3285-15C>T is intronic with protein consequence p.?, so no amino-acid residue can be evaluated for a missense critical domain.	cspec
PM2	Not met	Not met: the highest gnomAD subpopulation frequency is 0.0409475%, exceeding the ATM VCEP PM2 threshold of <=0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no A-T proband, biallelic observation, pathogenic variant in trans, or phase evidence was reported; the VCEP table has no entry for this variant.	cspec vcep_atm_pm3_bp2_1_5 gnomad_v4
PM4	N/A	Not applicable: ATM VCEP PM4 is restricted to stop-loss variants, whereas c.3285-15C>T is intronic with no protein-length change.	cspec
PM5	N/A	Not applicable: ATM PM5 requires an eligible truncating or same-residue missense comparator, whereas c.3285-15C>T is intronic with protein consequence p.?.	cspec pm5_candidates
PM6	N/A	Not applicable: the governing ATM VCEP version 1.6 explicitly designates PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation, parental testing, or informative meiosis data are reported for NM_000051.4:c.3285-15C>T.	cspec
PP2	N/A	Not applicable: the ATM VCEP marks PP2 Not Applicable, and c.3285-15C>T is intronic rather than a missense variant.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.01 is below the ATM VCEP PP3 threshold of >=0.2.	cspec spliceai
PP4	N/A	Not applicable: the ATM VCEP prohibits separate PP4 use for both ATM-related cancer predisposition and ataxia-telangiectasia.	cspec
PP5	N/A	Not applicable: the ATM VCEP prohibits PP5, and no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists.	cspec clinvar
BA1	Not met	Not met: gnomAD grpmax FAF is 0.022392% in v2.1, below the ATM VCEP BA1 threshold of >0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 grpmax FAF is 0.022392%, below the ATM VCEP BS1 threshold of >0.05%.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly designates BS2 as not applicable, despite zero observed homozygotes in available gnomAD datasets.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific rescue result was found, and ATM VCEP BS3 requires an exact tested-variant readout showing rescue of an ATM feature or radiosensitivity.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable: the governing ATM VCEP version 1.6 explicitly designates BS4 as Not Applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 Not Applicable, and c.3285-15C>T is intronic rather than a missense variant.	cspec
BP2	Not assessed	Not assessed: no unaffected adult carrying a pathogenic ATM variant in trans, or phase evidence, was reported; the VCEP table has no entry for this variant.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable, and this variant is intronic rather than an in-frame repeat-region indel.	cspec
BP4	Met	Met, supporting: SpliceAI maximum delta 0.01 meets the ATM VCEP BP4 threshold of <=0.1.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because alternate pathogenic variants do not reliably distinguish the phenotype in this low-penetrance disorder.	cspec
BP6	N/A	Not applicable: the ATM VCEP prohibits BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: c.3285-15C>T is intronic, whereas BP7 is restricted here to synonymous variants.	cspec

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