Variant classification summary

NM_000051.4:c.838A>G

ATM · NP_000042.3:p.(Ile280Val) · NM_000051.4

GRCh37: chr11:108115690 A>G · GRCh38: chr11:108244963 A>G

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.(Ile280Val)

gnomAD AF

1.8596324622401628e-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 0.000186% (3/1,613,222 alleles) is below the 0.001% threshold, confirming the variant is extremely rare.

2

BP4 (Supporting): REVEL 0.043 is well below the 0.249 missense threshold, indicating a benign-leaning computational effect.

3

Final: PM2 supporting (pathogenic side) combined with BP4 supporting (benign side) satisfies the conflicting-evidence rule, giving VUS (uncertain significance).

Final determination: Under the ClinGen HBOP ATM VCEP v1.5 combination rules, Rule31 (at least one benign-supporting criterion, BP4 supporting, together with at least one pathogenic-supporting criterion, PM2 supporting) is the only satisfied rule and yields Uncertain Significance - Conflicting Evidence, so the variant is classified as VUS; no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule is satisfied.

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.838A>G is a missense change p.(Ile280Val), not a null variant, so the loss-of-function rule does not apply.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment spliceai
PS1	Not met	Not met: no established pathogenic or likely pathogenic variant producing p.Ile280Val exists; ClinVar lists only uncertain significance for this variant.	cspec clinvar pm5_candidates spliceai
PS2	N/A	Not applicable: the ATM expert panel does not use de novo evidence for this recessive condition.	cspec
PS3	Not assessed	Not assessed: the only functional measurement available (Sun 2025) was equivocal, 'Intermediate', not a confirmed failure to rescue an ATM function. Flagged for human review: the assay is not approved by the ATM expert panel.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:32761968 PMID:34262154
PS4	Not met	Not met: no case-control study of this exact variant exists; the only case-control ATM study in the literature does not list c.838A>G.	cspec PMID:34262154 PMID:32761968
PM1	N/A	Not applicable: the ATM expert panel does not use the mutational-hotspot criterion for this gene.	cspec
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency 0.000186% (3/1,613,222 alleles) is far below the 0.001% threshold.	gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3	Not assessed	Not assessed: no ataxia-telangiectasia proband observations of this variant (homozygous or in trans) were available.	vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4 PMID:32761968 PMID:34262154
PM4	N/A	Not applicable: this rule covers only stop-loss variants, and p.Ile280Val is a missense change.	cspec
PM5	N/A	Not applicable: the ATM panel's PM5 applies only to truncating variants upstream of p.Arg3047; this is a missense change.	cspec pm5_candidates
PM6	N/A	Not applicable: the ATM expert panel does not use presumed-de-novo evidence for this recessive condition.	cspec
PP1	Not assessed	Not assessed: no family segregation data for this variant were available (no affected relatives genotyped).	cspec
PP2	N/A	Not applicable: the ATM expert panel does not use the missense-mechanism criterion for this gene.	cspec
PP3	Not met	Not met: REVEL 0.043 is far below the 0.7333 threshold, and SpliceAI 0.01 is far below 0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM panel routes phenotype evidence through its PM3/BP2 points system instead of this criterion.	cspec
PP5	N/A	Not applicable: ClinVar labels this variant uncertain significance with no expert-panel pathogenic classification.	cspec clinvar
BA1	Not met	Not met: grpmax filtering allele frequency 0.000553% is roughly 900-fold below the 0.5% threshold.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: grpmax filtering allele frequency 0.000553% is about 90-fold below the 0.05% threshold.	gnomad_v4 gnomad_v2 cspec
BS2	N/A	Not applicable: the ATM panel captures unaffected-carrier observations through its PM3/BP2 points system instead.	cspec
BS3	Not assessed	Not assessed: the only functional measurement available (Sun 2025) was equivocal, 'Intermediate', not a confirmed rescue of function. Flagged for human review: the assay is not approved by the ATM expert panel.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 PMID:32761968 PMID:34262154
BS4	N/A	Not applicable: the ATM panel excludes lack-of-segregation evidence for this condition, and no family genotyping data existed.	cspec
BP1	N/A	Not applicable: the ATM expert panel does not use the truncating-only-disease criterion for this gene.	cspec
BP2	Not assessed	Not assessed: no unaffected carriers of this variant with a pathogenic ATM variant in trans were documented.	vcep_atm_pm3_bp2_1_5 cspec clinvar PMID:32761968 PMID:34262154
BP3	N/A	Not applicable: the variant is a missense change with no insertion, deletion, or repeat-region context.	cspec
BP4	Met	Met (supporting): REVEL 0.043 is well below the 0.249 missense threshold; SpliceAI 0.01 also rules out splice impact.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 bayesdel
BP5	N/A	Not applicable: the ATM expert panel does not use the alternate-molecular-basis criterion.	cspec
BP6	N/A	Not applicable: ClinVar labels this variant uncertain significance with no expert-panel benign classification.	cspec clinvar
BP7	N/A	Not applicable: this rule covers synonymous and deep-intronic variants, and p.Ile280Val is a missense exonic change.	cspec

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