Variant classification summary

NM_000051.4:c.3332T>C

ATM · NP_000042.3:p.(Leu1111Pro) · NM_000051.4

GRCh37: chr11:108150265 T>C · GRCh38: chr11:108279538 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1111Pro)

gnomAD AF

3.0984309545646086e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is extremely rare in population databases — gnomAD v4.1 total allele frequency 0.00031% (5 of 1,613,720 alleles), below the VCEP's 0.001% threshold, with no homozygotes.

2

BP4 (Supporting): no predicted splicing impact (SpliceAI max delta 0.01, below the 0.1 threshold).

3

Overall classification: VUS. One pathogenic-supporting and one benign-supporting criterion (VCEP Rule 31) produce 'Uncertain Significance - Conflicting Evidence'.

Final determination: VCEP Rule31 of the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework: at least one benign-supporting criterion (BP4 supporting) plus at least one pathogenic-supporting criterion (PM2 supporting) is satisfied and no higher-strength pathogenic or benign combination rule applies, so the variant is classified as Uncertain Significance (VUS; 'Uncertain Significance - Conflicting Evidence' per the ruleset).

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	PVS1 does not apply: this is a missense substitution (p.Leu1111Pro), not a null variant (nonsense, frameshift, canonical splice-site, initiation-codon, or whole-exon deletion), and the splicing predictor SpliceAI predicts no effect on splicing (max delta 0.01). Although loss of ATM function is an established disease mechanism, PVS1 is reserved for null variants under the ATM VCEP.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context spliceai clinvar
PS1	Not met	PS1 is not met: no established pathogenic or likely pathogenic classification exists for this exact amino acid change. All seven clinical laboratory submissions in ClinVar classify p.Leu1111Pro as Uncertain significance, and no pathogenic variant at residue 1111 has been reported.	clinvar pm5_candidates spliceai PMID:25741868
PS2	N/A	PS2 does not apply: the ATM VCEP does not use de novo reasoning for this gene, and no de novo occurrence or parental-testing data exist for this variant.	cspec
PS3	Not assessed	Insufficient evidence was available to assess PS3: the variant was not tested in any of the VCEP-approved functional assays, and no failure-of-rescue result exists. The only direct functional data, a prime-editing saturation screen (Sun et al. 2025), classified the variant as retaining ATM function, which argues against a damaging effect rather than supporting PS3.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 oncokb clinvar PMID:25741868
PS4	Not met	PS4 is not met: no case-control or cohort enrichment study of this variant has been reported. The available literature consists of guidelines, reviews, and a functional assay; a single somatic observation in COSMIC does not constitute germline case-control enrichment.	cspec clinvar PMID:17508274 PMID:40580951
PM1	N/A	PM1 does not apply: the ATM VCEP declares it not applicable. Independently, residue 1111 is not in a statistically significant cancer hotspot and lies outside the kinase-domain region.	cspec
PM2	Met	PM2 is met at supporting strength: the variant is extremely rare in population databases, with a gnomAD v4.1 total allele frequency of 0.00031% (5 of 1,613,720 alleles) — below the VCEP's 0.001% threshold — and no homozygotes in any dataset.	gnomad_v4 gnomad_v2 clinvar cspec
PM3	Not assessed	Insufficient evidence was available to assess PM3: this variant has not been reported in any Ataxia-Telangiectasia proband, and no data exist on a second ATM alteration on the opposite chromosome (allelic phase), so the VCEP's points-based threshold could not be evaluated.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4 gnomad_v2 PMID:40580951 PMID:25741868 PMID:34242744 PMID:17508274
PM4	N/A	PM4 does not apply: the variant is a missense substitution that leaves protein length unchanged; it is neither a stop-loss variant nor an in-frame insertion/deletion.	cspec clinvar PMID:25741868
PM5	N/A	PM5 does not apply: under the ATM VCEP, PM5 is restricted to truncating variants with premature stop codons upstream of p.Arg3047 and is explicitly not used for missense changes. No pathogenic missense variant at residue 1111 has been reported either.	cspec pm5_candidates PMID:25741868
PM6	N/A	PM6 does not apply: the ATM VCEP does not use assumed-de-novo reasoning, and no parental-testing data exist for this variant.	cspec
PP1	Not assessed	Insufficient evidence was available to assess PP1: no family-segregation data were documented — no affected relatives tested, no meioses reported, and no non-segregation observations — so no segregation strength could be assigned.	cspec
PP2	N/A	PP2 does not apply: the ATM VCEP declares it not applicable.	cspec
PP3	Not met	PP3 is not met: the in-silico predictor REVEL scores the variant 0.644, below the VCEP's 0.7333 threshold, and SpliceAI predicts no splicing impact (max delta 0.01, below the 0.2 threshold).	revel spliceai bayesdel cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	PP4 does not apply: the ATM VCEP declares it not applicable; phenotype specificity for Ataxia-Telangiectasia is instead captured through the VCEP's PM3/BP2 points table.	cspec
PP5	N/A	PP5 does not apply: the ClinVar record is an aggregate Uncertain significance classification from seven laboratories with no expert-panel submission, which does not meet the three-star expert-panel requirement.	clinvar cspec
BA1	Not met	BA1 is not met: the variant's population frequency is far below the 0.5% threshold — gnomAD v4.1 filtering allele frequency 0.000124% and total allele frequency 0.00031%, with no homozygotes.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	BS1 is not met: the highest population-specific frequency (0.00042% in European non-Finnish individuals) is below the VCEP's 0.05% threshold.	gnomad_v4 gnomad_v2 cspec
BS2	N/A	BS2 does not apply: the ATM VCEP lists it as not applicable.	cspec
BS3	Not assessed	Insufficient evidence was available to assess BS3: the variant was not tested in any of the VCEP-approved functional assays, so no calibrated rescue result exists. A saturation-screen study (Sun et al. 2025) classified the variant as retaining ATM function, which points toward BS3, but that assay is not among those the VCEP has calibrated and no radiosensitivity data exist; the evidence is therefore insufficient for BS3 on currently available data.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 oncokb clinvar PMID:25741868
BS4	N/A	BS4 does not apply: the ATM VCEP declares it not applicable, and no non-segregation data (affected relatives testing negative for the variant) exist.	cspec
BP1	N/A	BP1 does not apply: the ATM VCEP declares it not applicable, and missense variants can cause ATM-related disease, so the generic rule for genes in which only truncating variants are pathogenic would not apply in any case.	cspec pvs1_gene_context
BP2	Not assessed	Insufficient evidence was available to assess BP2: no unaffected-carrier or in-trans observations (an individual carrying this variant opposite a pathogenic ATM variant) were documented, so the VCEP's points-based BP2 could not be evaluated.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4 gnomad_v2 PMID:40580951 PMID:25741868 PMID:34242744 PMID:17508274
BP3	N/A	BP3 does not apply: the ATM VCEP declares it not applicable, and the variant is a missense substitution rather than an in-frame insertion/deletion in a repeat region.	cspec PMID:25741868
BP4	Met	BP4 is met at supporting strength via the splicing sub-path: SpliceAI predicts no splicing impact (max delta 0.01, below the 0.1 threshold). The missense sub-path (REVEL of 0.644 is not at or below 0.249) was not met.	spliceai revel bayesdel cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	BP5 does not apply: the ATM VCEP declares it not applicable, and no data on an alternate molecular basis of disease were available.	cspec
BP6	N/A	BP6 does not apply: no expert panel has classified this variant as benign or likely benign — the ClinVar record is Uncertain significance from seven laboratories with no expert-panel submissions.	clinvar cspec
BP7	N/A	BP7 does not apply: it is restricted to synonymous and deep intronic variants, and this variant is a missense exonic change.	cspec

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