Variant classification summary

NM_000051.4:c.2522A>C

ATM · NP_000042.3:p.(Asp841Ala) · NM_000051.4

GRCh37: chr11:108137953 A>C · GRCh38: chr11:108267226 A>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asp841Ala)

gnomAD AF

7.867810865260951e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The variant NM_000051.4:c.2522A>C (p.Asp841Ala) is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.1156% (127 alleles, including 3 homozygotes), exceeding the ATM VCEP BS1_Strong threshold of >0.05%. This population frequency is incompatible with a highly penetrant pathogenic ATM variant.

2

Computational predictors are consistent with a benign effect: REVEL score is 0.139 (below the BP4_Supporting threshold of ≤0.249), SpliceAI predicts no splice impact (max delta = 0.00), and BayesDel score is -0.415893 (benign range).

3

The VCEP ATM functional scoring table (Suppl_TableS1, PMID 40580951) classifies D841A as 'Functional' with high confidence, placing it in the non-damaging category among ATM missense variants.

4

No variant-specific functional evidence supporting pathogenicity was identified in the literature; six full-text papers were reviewed and none mention this variant.

Final determination: Rule18 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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 is restricted to null variants (nonsense, frameshift, canonical splice sites); NM_000051.4:c.2522A>C is a missense variant (p.Asp841Ala) and does not qualify for PVS1 under the ATM VCEP PVS1 decision tree.	vcep_atm_pvs1_1_5
PS1	Not met	PS1 requires a previously established pathogenic missense change at the same residue. All alternative substitutions at Asp841 (D841V, D841G, D841Y, D841N, D841H, D841E) are classified as Uncertain significance or Conflicting classifications in ClinVar and as 'Functional' (not pathogenic) in the VCEP functional scoring table (Suppl_TableS1). No pathogenic comparator exists at this residue.	clinvar vcep_suppl_tables1_pmid_40580951
PS2	N/A	Per ATM VCEP v1.5.0, PS2 is not applicable for ATM: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific functional studies were identified for NM_000051.4:c.2522A>C (p.Asp841Ala) in the literature reviewed. The VCEP functional spreadsheet (Suppl_TableS1) classifies D841A as 'Functional' based on in silico prediction, not experimental functional assay data. No published functional assay includes this specific variant.	vcep_suppl_tables1_pmid_40580951
PS4	Not met	PS4 requires case-control studies demonstrating significant enrichment in affected individuals. No case-control study or proband enrichment analysis was identified for this variant. The variant is observed at appreciable population frequency (gnomAD v4.1 AF=0.00787%, 127 alleles, 3 homozygotes), inconsistent with a highly penetrant pathogenic variant enriched in cases.	gnomad_v4
PS5	N/A	PS5 is not defined in the ATM VCEP v1.5.0 criteria set. Under generic ACMG/AMP, PS5 requires a reputable source to report the variant as pathogenic; ClinVar classifies this variant as Likely benign / Uncertain significance with no expert panel pathogenic assertion.	cspec clinvar
PM1	N/A	Per ATM VCEP v1.5.0, PM1 is not applicable: benign and pathogenic variants occur within the same domains and germline mutational hotspots are not well defined at this time.	cspec
PM2	Not met	ATM VCEP PM2_Supporting requires allele frequency ≤0.001% in gnomAD v4. This variant has AF=0.00787% (127/1,614,172 alleles) in gnomAD v4.1, exceeding the PM2 threshold.	gnomad_v4 cspec
PM5	N/A	ATM VCEP PM5_Supporting is restricted to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with PVS1_Strength(RNA). PM5 is explicitly not for use with missense changes per VCEP instructions.	cspec pm5_candidates
PM6	N/A	Per ATM VCEP v1.5.0, PM6 is not applicable for ATM: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not assessed	No segregation data are available for this variant. ATM VCEP PP1 applies to autosomal recessive (A-T) conditions with affected relatives; no proband or family segregation information was identified.
PP2	N/A	Per ATM VCEP v1.5.0, PP2 is not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	ATM VCEP PP3_Supporting for missense variants requires REVEL score >0.7333. The REVEL score for c.2522A>C (p.Asp841Ala) is 0.139, well below the threshold. SpliceAI max delta score is 0.00, also not meeting the splicing prediction threshold (≥0.2).	revel spliceai cspec vcep_suppl_tables1_pmid_40580951
PP4	N/A	Per ATM VCEP v1.5.0, PP4 is not applicable: breast cancer has multiple genetic etiologies (genetic heterogeneity) with no features that can readily distinguish hereditary from sporadic causes. For A-T, evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	Per ATM VCEP v1.5.0, PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	ATM VCEP BA1 requires grpmax filtering allele frequency >0.5% in gnomAD v4. The grpmax FAF for this variant is 0.1156%, which is below the BA1 threshold.	gnomad_v4 cspec
BS1	Met	ATM VCEP BS1_Strong is met: grpmax filtering allele frequency in gnomAD v4.1 is 0.1156%, exceeding the >0.05% threshold. The variant is present in 127 alleles including 3 homozygotes in v4.1, and 43 alleles including 1 homozygote in v2.1, with highest frequency in the South Asian population (v4.1 AF=0.135%). This population frequency is incompatible with a highly penetrant pathogenic ATM variant.	gnomad_v4 gnomad_v2 cspec
BS2	N/A	Per ATM VCEP v1.5.0, BS2 is not applicable: ATM has incomplete penetrance.	cspec
BS3	Not met	No variant-specific benign functional evidence was identified. The VCEP functional spreadsheet classifies D841A as 'Functional' based on computational prediction, not experimental assay data. No published experimental study (ATM kinase assay, radiosensitivity assay) includes c.2522A>C.	vcep_suppl_tables1_pmid_40580951
BS4	N/A	Per ATM VCEP v1.5.0, BS4 is not applicable: co-segregation analysis in low-penetrance genes can lead to false positive results, and informative lack of co-segregation in A-T families is too rare.	cspec
BP1	N/A	Per ATM VCEP v1.5.0, BP1 is not applicable: missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	BP2 requires proband data evaluated through the ATM PM3/BP2 point table. No proband-level data (A-T affected or unaffected individuals with phased genotypes) were available for this variant. The 3 homozygotes in gnomAD v4.1 suggest potential BP2 applicability but formal assessment requires individual-level phenotype confirmation and use of the VCEP PM3/BP2 scoring table.	gnomad_v4 vcep_atm_pm3_bp2_1_5
BP3	N/A	Skipped: in-frame deletions/insertions in repetitive regions; not applicable to this substitution variant.
BP4	Met	ATM VCEP BP4_Supporting for missense variants is met: REVEL score is 0.139, which is ≤0.249. Additionally, SpliceAI predicts no splice impact (max delta = 0.00, ≤0.1), and BayesDel score is -0.415893 (benign range). Multiple computational lines of evidence suggest no deleterious effect.	revel spliceai bayesdel cspec vcep_suppl_tables1_pmid_40580951
BP5	N/A	Per ATM VCEP v1.5.0, BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance.	cspec
BP6	N/A	Per ATM VCEP v1.5.0, BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous and deep intronic variants. NM_000051.4:c.2522A>C is a missense variant (p.Asp841Ala) and does not qualify for BP7.	cspec

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