Variant classification summary

NM_000051.4:c.5868C>T

ATM · NP_000042.3:p.(Leu1956=) · NM_000051.4

GRCh37: chr11:108180992 C>T · GRCh38: chr11:108310265 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1956=)

gnomAD AF

1.301636218709595e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BP4 supporting - SpliceAI maximum delta score 0.053 is at or below the ATM VCEP's <=0.1 no-predicted-splice-impact cutoff for a synonymous variant.

2

Likely Benign: BP7 supporting - synonymous p.(Leu1956=) sits 55-110 nt from the nearest splice site, outside the +7/-21 window, with no predicted splice impact.

Final determination: Under the ClinGen HBOP ATM Expert Panel v1.6 criteria-combination framework, two benign supporting criteria (Benign.Supporting >=2, Rule19) - BP4 supporting and BP7 supporting - are satisfied and give a classification of 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: c.5868C>T is synonymous (p.Leu1956=), not a PVS1 null variant, and SpliceAI max delta 0.053 predicts no splice defect.	cspec vcep_atm_pvs1_1_5 vcep_atm_pvs1_1_6 spliceai pvs1_gene_context pvs1_variant_assessment
PS1	Not met	Not met: c.5868C>T is synonymous with SpliceAI max delta 0.053, below the 0.2 threshold needed to enter the PS1 splicing table, and no pathogenic variant exists at residue 1956.	cspec vcep_atm_ps1_1_5 vcep_atm_ps1_1_6 spliceai vcep_suppl_tables1_pmid_40580951 PMID:25741868
PS2	N/A	Not applicable: the ATM VCEP v1.6 specification excludes PS2 outright, stating informative de novo occurrences have not been observed for ATM.	cspec
PS3	Not met	Not met: the only Table S1 entry for c.5868C>T is DeepATM_predicted=Yes, a computational extrapolation, so no functional assay supports PS3.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec
PS4	Not met	Not met: no case-control study exists for c.5868C>T, so the VCEP-required p ≤ 0.05 with odds ratio or relative risk ≥ 2 cannot be shown.	cspec clinvar gnomad_v2 PMID:25741868 PMID:24366376 PMID:24366402 PMID:25394175 PMID:31429903
PM1	N/A	Not applicable: the ClinGen HBOP ATM VCEP designates PM1 unusable because benign and pathogenic variants occur in the same domains.	cspec
PM2	Not met	Not met: highest gnomAD subpopulation frequency 0.0294% (South Asian) is ~29-fold above the ATM VCEP's <=0.001% PM2 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not met	Not met: zero PM3 points from unrelated A-T probands (VCEP threshold 1 point), and gnomAD grpmax filtering AF 0.0118% exceeds the VCEP's 0.01% PM3 frequency ceiling.	cspec vcep_atm_pm3_bp2_1_5 vcep_atm_pm3_bp2_1_6 gnomad_v2 gnomad_v4 clinvar
PM4	N/A	Not applicable: the ATM VCEP restricts PM4 to stop-loss variants, and p.Leu1956= is synonymous with no protein-length change.	cspec
PM5	Not met	Not met: PM5 applies only to NMD-prone truncating variants receiving PVS1 at Very Strong, and c.5868C>T is a synonymous change with no premature stop codon.	cspec pm5_candidates vcep_suppl_tables1_pmid_40580951
PM6	N/A	Not applicable: the ATM VCEP v1.6 specification excludes PM6, so an unconfirmed de novo is never scored for ATM.	cspec
PP1	Not assessed	Not assessed: no affected-relative genotypes or pedigree data exist, so PP1's autosomal-recessive threshold of >=1 affected relative cannot be tested.	cspec clinvar
PP2	N/A	Not applicable: the ATM VCEP excludes PP2 because ATM has no defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.053 is below the ATM VCEP PP3 supporting threshold of >=0.2.	cspec spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP v1.6 prohibits PP4 for both the dominant cancer and recessive ataxia-telangiectasia phenotypes.	cspec
PP5	Not met	Not met: ClinVar VCV000453600 has zero expert-panel submissions, all seven entries being single-submitter laboratory assertions, so PP5 cannot trigger.	cspec clinvar
BA1	Not met	Not met: highest gnomAD Grpmax Filtering AF 0.0153% versus the ATM VCEP's >0.5% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest gnomAD Grpmax Filtering AF 0.0153% versus the ATM VCEP's >0.05% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the governing ATM VCEP lists BS2 as Not Applicable and no gnomAD dataset reports a homozygote.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Not met: the sole Table S1 entry for c.5868C>T is a computational prediction (DeepATM_predicted=Yes), not a measured rescue of ATM function.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec
BS4	N/A	Not applicable: the ATM VCEP v1.6 specification excludes BS4, noting informative non-segregation in A-T families is too rare to carry weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP excludes BP1 because pathogenic missense variants are known to occur in ATM.	cspec
BP2	Not met	Not met: zero BP2 points — no unaffected adult carrier in trans with a pathogenic ATM variant, and gnomAD reports 0 homozygotes (threshold -1 point).	cspec vcep_atm_pm3_bp2_1_5 vcep_atm_pm3_bp2_1_6 gnomad_v4 gnomad_v2 clinvar
BP3	N/A	Not applicable: the ATM VCEP marks BP3 Not Applicable, and c.5868C>T is a synonymous substitution rather than an in-frame repeat-region indel.	cspec
BP4	Met	Met at supporting: SpliceAI maximum delta 0.053 is at or below the ATM VCEP BP4 no-impact threshold of <=0.1.	cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP v1.6 instructs against BP5 because ATM is low-penetrance and co-occurring pathogenic variants are common.	cspec
BP6	Not met	Not met: no expert-panel ClinVar classification exists for c.5868C>T; the aggregate two-star Benign/Likely benign label from seven laboratories does not qualify.	cspec clinvar
BP7	Met	Met at supporting: synonymous p.Leu1956= variant, 55-110 nt from the nearest splice site, with SpliceAI maximum delta 0.053 showing no splice impact.	cspec spliceai vcep_suppl_tables1_pmid_40580951

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