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

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): gnomAD v4.1 allele frequency 3.098e-06 (0.00031%) is below the VCEP's 0.001% threshold, with no homozygotes observed.

2

Overall classification: Variant of Uncertain Significance — under the ClinGen HBOP ATM VCEP v1.5 ruleset, PM2_Supporting alone does not match any combination rule.

Final determination: Under the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework, a variant is classified only when a combination rule (Rules 1-20, conflict rules 21-32) matches the applied criteria; with only PM2 supporting applied and no Very Strong, Strong, Moderate, or benign criterion present, no rule matches and the variant is classified Variant of Uncertain Significance.

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: this is a missense substitution, not a null variant (nonsense, frameshift, canonical splice, or exon deletion), so the PVS1 decision tree does not apply.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not assessed	Not assessed: insufficient evidence was available to evaluate this missense change against an established pathogenic variant at the same position.
PS2	N/A	Not applicable: the ATM VCEP rules do not use de novo evidence, and no parental or trio testing data were available.	cspec
PS3	Not met	Not met: a direct functional assay found the variant retains function (Sun et al. 2025, 'Functional', high confidence), so no damaging-effect evidence supports PS3.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:40580951 vcep_suppl_tables1_pmid_40580951
PS4	Not met	Not met: no case-control or cohort enrichment study of this variant exists, so the PS4 requirements (p<=0.05 and OR>=2) cannot be met.	cspec clinvar gnomad_v4 PMID:25741868 PMID:34242744 PMID:24366402 PMID:20301425 PMID:40580951
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether this position falls in a mutational hotspot or critical domain.
PM2	Met	Met (Supporting): gnomAD v4.1 allele frequency 3.1e-06 (0.00031%) is below the VCEP's 0.001% supporting threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Not assessed	Not assessed: no evidence places this variant in an affected A-T proband (all ClinVar submissions are VUS), so no PM3 points could be accrued.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4
PM4	N/A	Not applicable: the VCEP restricts PM4 to stop-loss variants, and p.Leu1111Pro is a missense change that does not extend the protein.	cspec
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether a different pathogenic variant occurs at the same codon.
PM6	N/A	Not applicable: the ATM VCEP rules do not use unconfirmed de novo evidence, and no parental identity testing data were available.	cspec
PP1	Not assessed	Not assessed: no segregation or pedigree evidence was available — zero informative meioses — so no PP1 strength could be assigned.	cspec
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate whether missense variants in ATM are a common disease mechanism.
PP3	Not met	Not met: REVEL 0.644 is below the >0.7333 PP3 threshold, and SpliceAI max delta 0.01 is below 0.2.	revel spliceai vcep_suppl_tables1_pmid_40580951 cspec
PP4	N/A	Not applicable: the ATM VCEP captures phenotype specificity through its PM3/BP2 points table instead, and no proband phenotype data were available.	cspec
PP5	N/A	Not applicable: ClinVar labels this variant 'Uncertain significance' with no expert-panel classification, so PP5 does not trigger.	clinvar cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 1.24e-06 (0.000124%) is about 4000-fold below the 0.5% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF 1.24e-06 (0.000124%) is about 400-fold below the 0.05% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS2	N/A	Not applicable: the ATM VCEP marks BS2 as not applicable; no population homozygotes were observed (0 in gnomAD v4.1 and v2.1).	cspec
BS3	Not assessed	Not assessed: the sole functional assay (Sun et al. 2025, 'Functional') is not among the VCEP-approved assays, so no calibrated BS3 strength could be assigned. Flagged for human review.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:40580951 vcep_suppl_tables1_pmid_40580951 oncokb
BS4	N/A	Not applicable: the ATM VCEP marks BS4 as not applicable, and no non-segregation data were available.	cspec
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether this variant lies outside a critical protein domain.
BP2	Not assessed	Not assessed: no unaffected carrier in trans with a pathogenic variant was documented, so no BP2 points could be accrued.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4
BP3	N/A	Not applicable: the ATM VCEP marks BP3 as not applicable, and this missense substitution is not an in-frame repeat-region indel.	cspec
BP4	Not met	Not met: REVEL 0.644 is above the <=0.249 BP4 threshold; missense variants are evaluated on the REVEL sub-path only.	revel spliceai vcep_suppl_tables1_pmid_40580951 cspec
BP5	N/A	Not applicable: the ATM VCEP marks BP5 as not applicable, and no alternate molecular basis of disease was documented.	cspec
BP6	N/A	Not applicable: ClinVar labels this variant 'Uncertain significance' with no expert-panel classification, so BP6 does not trigger.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies to synonymous and deep intronic variants, and p.Leu1111Pro is a missense substitution.	cspec

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