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): extremely rare in population databases - gnomAD v4.1 allele frequency 0.00019% (3/1,613,222 alleles), no homozygotes, far below the panel's 0.001% threshold.

2

BP4 (Supporting): computational prediction strongly favors a benign effect - REVEL 0.043, well below the panel's 0.249 threshold.

3

Final classification: VUS (Uncertain Significance - Conflicting Evidence), produced by Rule 31 (one pathogenic-supporting criterion plus one benign-supporting criterion).

Final determination: Under the ClinGen HBOP ATM VCEP v1.5 criteria-combination framework, Rule31 (at least one Benign.Supporting criterion AND at least one Pathogenic.Supporting criterion) is satisfied by BP4 supporting + PM2 supporting, so the variant is classified as Uncertain Significance - Conflicting Evidence (VUS).

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 change (p.Ile280Val), not a gene-disrupting (null) variant, and the ATM expert panel limits PVS1 to nonsense, frameshift, splice-site, and deletion variants. Splicing predictions show no impact, so there is no loss-of-function route via splicing either.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not met	Not met: PS1 requires an established pathogenic variant producing the identical amino acid change (p.Ile280Val), and none exists. ClinVar lists only six 'Uncertain significance' submissions for this variant, and no publication reports this exact change.	cspec vcep_atm_ps1_1_5 clinvar pm5_candidates PMID:25741868
PS2	N/A	Not applicable: ATM disease in this case is autosomal recessive (Ataxia Telangiectasia), and the ATM expert panel disallows de novo evidence for this inheritance pattern. No de novo occurrence data were available for this variant in any case.	cspec
PS3	Not met	Not met: no functional assay approved by the ATM expert panel has tested this variant. The only direct measurement (Sun et al. 2025) classified it 'Intermediate' - not non-functional - so it does not demonstrate loss of ATM function.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec oncokb
PS4	Not met	Not met: no variant-specific case-control enrichment exists for c.838A>G. The one case-control study available found enrichment of grouped ATM variants in melanoma cases but did not include this variant.	PMID:34262154 PMID:35534704 PMID:32761968 PMID:24418350 PMID:25394175 PMID:25741868 cspec
PM1	N/A	Not applicable: the ATM expert panel defines no mutational-hotspot rule for this gene, and no statistically significant cancer hotspot includes residue 280.	cspec
PM2	Met	Met (supporting): the variant is extremely rare, with a gnomAD v4.1 allele frequency of 0.00019% (3/1,613,222 alleles), no homozygotes, and all subpopulation frequencies far below the panel's 0.001% threshold; gnomAD v2.1 shows a similarly low frequency.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not met	Not met: no Ataxia-Telangiectasia proband carrying this variant was identified. ClinVar submissions are all 'Uncertain significance' with no proband case data, and no publication reports the variant, so the points-based rule earns zero points.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4 gnomad_v2 PMID:32761968 PMID:34262154 PMID:35534704
PM4	N/A	Not applicable: the ATM panel scopes PM4 to stop-loss variants. This is a single conservative amino acid substitution (isoleucine to valine) with no change in protein length.	cspec
PM5	N/A	Not applicable: under the ATM panel's rules, PM5 applies to truncating variants, not missense changes. No pathogenic alternate missense at residue 280 exists in ClinVar or the literature in any case.	cspec pm5_candidates clinvar
PM6	N/A	Not applicable: as with PS2, the ATM expert panel disallows assumed de novo evidence for autosomal recessive disease, and no de novo occurrence data exist for this variant.	cspec
PP1	Not assessed	Not assessed: no family segregation data (genotyped affected relatives, pedigree, or phase information) were available for this variant, and no publication reports it. Segregation evidence would be needed before this criterion can be scored.	cspec
PP2	N/A	Not applicable: the ATM expert panel defines no PP2 (missense mechanism) rule for this gene.	cspec
PP3	Not met	Not met: both computational sub-paths defined by the ATM panel fail. REVEL is 0.043, far below the 0.7333 threshold, and SpliceAI predicts no splicing impact (score 0.00 versus a 0.2 threshold).	revel spliceai bayesdel cspec
PP4	N/A	Not applicable: the ATM expert panel routes phenotype evidence through its PM3/BP2 points system rather than PP4, and no proband phenotype information was available.	cspec
PP5	N/A	Not applicable: the ATM expert panel disallows PP5, and no expert panel has classified this exact variant - ClinVar contains only six clinical-laboratory 'Uncertain significance' submissions, which cannot trigger PP5.	clinvar cspec
BA1	Not met	Not met: the variant is far too rare for this stand-alone benign criterion. Its gnomAD v4.1 frequency (0.00019%) is roughly 900-fold below the 0.5% threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: population frequency does not approach the strong-benign threshold - 0.00019% versus the required 0.05%.	gnomad_v4 gnomad_v2
BS2	N/A	Not applicable: the ATM panel routes homozygous and in-trans observations in unaffected individuals through its PM3/BP2 points table instead. No homozygotes for this variant were observed in gnomAD in any case.	cspec gnomad_v4 gnomad_v2
BS3	Not met	Not met: no assay approved by the ATM expert panel shows this variant preserves ATM function. The only direct measurement (Sun et al. 2025) classified it 'Intermediate' - not functional.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec oncokb
BS4	N/A	Not applicable: the ATM panel disallows BS4 for this autosomal recessive condition, as informative lack-of-segregation observations are considered too rare to carry benign weight. None exist for this variant in any case.	cspec
BP1	N/A	Not applicable: the ATM expert panel defines no rule assuming only truncating variants cause disease, consistent with missense variants being a recognized cause of ATM-related disease.	cspec
BP2	Not met	Not met: no unaffected carrier of this variant with a pathogenic ATM variant in trans was identified. ClinVar submissions carry no co-occurrence or phase data, gnomAD shows no homozygotes, and no publication reports the variant.	vcep_atm_pm3_bp2_1_5 clinvar gnomad_v4 gnomad_v2
BP3	N/A	Not applicable: the ATM panel retires BP3 ('do not use'), and in any case this is a single missense change, not an in-frame insertion/deletion in a repetitive region.	cspec
BP4	Met	Met (supporting): the REVEL score of 0.043 is well below the panel's 0.249 threshold, strongly predicting a benign effect on protein function; splicing prediction is likewise unremarkable.	revel spliceai bayesdel cspec
BP5	N/A	Not applicable: the ATM expert panel disallows BP5, and no alternate molecular basis for disease is documented for any carrier of this variant.	cspec
BP6	N/A	Not applicable: the ATM expert panel disallows BP6, and no expert panel has classified this variant as benign - all six ClinVar submissions are 'Uncertain significance' from clinical laboratories.	clinvar cspec
BP7	N/A	Not applicable: BP7 applies only to synonymous and deep intronic variants, and this is a missense change within the exon 7 coding sequence.	cspec

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