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 total allele frequency 0.00031% (5/1,613,720 alleles, 0 homozygotes) is below the VCEP 0.001% threshold, and the variant is absent from gnomAD v2.1.

2

Overall: Variant of Uncertain Significance — no VCEP combination rule matches a single supporting criterion with no other evidence.

Final determination: Under the ClinGen HBOP ATM VCEP v1.5 criteria-combination ruleset (cspec doc 639508985), the single met criterion PM2_Supporting satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule and no benign criterion is met to trigger a conflicting-evidence rule, so the variant is classified as 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: PVS1 covers only null variants, and this is a missense change (p.Leu1111Pro) with no predicted splice impact (SpliceAI max delta 0.01).	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not met	Not met: no established pathogenic variant producing p.Leu1111Pro exists — ClinVar lists this exact variant as uncertain significance (7 laboratories).	cspec vcep_atm_ps1_1_5 clinvar pm5_candidates
PS2	N/A	Not applicable: the ATM VCEP disallows PS2, and no de novo observation or parental testing is reported for this variant.	cspec
PS3	Not met	Not met: a directly measured functional screen shows the variant retains ATM function (classified Functional), the opposite of the loss-of-function evidence PS3 requires.	PMID:40580951 vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec clinvar oncokb
PS4	Not assessed	Insufficient evidence was available: no case-control or enrichment study of this variant has been published.	cspec
PM1	N/A	Not applicable: the ATM VCEP disallows PM1 because benign and pathogenic variants are known to occur in the same ATM domains.	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency 0.00031% (5/1,613,720 alleles, 0 homozygotes) is below the VCEP 0.001% threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Not assessed	Insufficient evidence was available: no ataxia telangiectasia proband genotyping data exists to assign PM3 points.	cspec vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, and this single-residue missense substitution produces no protein length change.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: the ATM VCEP restricts PM5 to truncating variants and explicitly excludes missense changes like p.Leu1111Pro.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM VCEP disallows PM6, and no assumed de novo observation exists for this variant.	cspec
PP1	Not assessed	Insufficient evidence was available: no family segregation data was reported for this variant.	cspec clinvar
PP2	N/A	Not applicable: the ATM VCEP disallows PP2 because ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: REVEL 0.644 is below the >0.7333 threshold, and SpliceAI max delta 0.01 is below the >=0.2 threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP disallows PP4 because breast cancer has multiple genetic etiologies and no distinguishing phenotype.	cspec
PP5	N/A	Not applicable: the ATM VCEP disallows PP5, and no expert-panel pathogenic classification exists for this variant (ClinVar: uncertain, 7 laboratories).	cspec clinvar
BA1	Not met	Not met: gnomAD grpmax allele frequency 0.000124% is about 4,000-fold below the >0.5% threshold.	gnomad_v4 cspec
BS1	Not met	Not met: gnomAD grpmax allele frequency 0.000124% is about 400-fold below the >0.05% threshold.	gnomad_v4 cspec
BS2	N/A	Not applicable: the ATM VCEP explicitly declares BS2 not applicable.	cspec
BS3	Not assessed	Insufficient evidence was available: the only functional result (variant retains ATM function) comes from an assay the ATM VCEP has not approved. Flagged for human review.	PMID:40580951 vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec clinvar oncokb
BS4	N/A	Not applicable: the ATM VCEP disallows BS4 because co-segregation analysis is unreliable in this low-penetrance gene.	cspec
BP1	N/A	Not applicable: missense variants are an established disease mechanism in ATM, so BP1 does not apply.	cspec
BP2	Not assessed	Insufficient evidence was available: no unaffected carrier of this variant with a pathogenic ATM variant in trans was reported.	cspec vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4
BP3	N/A	Not applicable: the ATM VCEP disallows BP3, and this missense variant is outside its repeat-region scope.	cspec
BP4	Not met	Not met: REVEL 0.644 exceeds the <=0.249 threshold; a recorded lab-curator override excludes the SpliceAI sub-path for missense variants.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP disallows BP5 because co-occurring variants are expected in this low-penetrance gene.	cspec
BP6	N/A	Not applicable: the ATM VCEP disallows BP6, and no expert-panel benign classification exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or deep intronic variants, and this is a coding missense change.	cspec

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