Variant classification summary

NM_000051.4:c.8787-26C>T

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108225512 C>T · GRCh38: chr11:108354785 C>T

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BP4 supporting benign BP7 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

0.00011136345151623216 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.8787-26C>T is a deep intronic variant located 26 nucleotides upstream of exon 60 in ATM. SpliceAI predicts no significant splice impact (max delta score 0.04).

2

BP7 (supporting) is applied per the ATM VCEP v1.5: the variant is intronic at position -26, which is further than the -21 acceptor site threshold for deep intronic variants.

3

BP4 (supporting) is applied per the ATM VCEP v1.5: SpliceAI predicts no splicing impact (max delta 0.04 ≤ 0.1 threshold).

4

The variant is present in gnomAD v4.1 at an allele frequency of 0.01114% (178/1,598,370 alleles) with no homozygotes. This frequency is above the VCEP PM2 threshold of ≤0.001% but below BS1 (>0.05%) and BA1 (>0.5%) thresholds.

5

The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, segregation data, or case-control studies are available.

6

Two supporting benign criteria are met (BP7, BP4) with no pathogenic criteria met. Per ACMG/AMP 2015 combination rules, ≥2 benign supporting criteria results in a classification of Likely Benign (Rule 19).

Final determination: Rule19 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 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	Not met	NM_000051.4:c.8787-26C>T is a deep intronic variant located 26 nucleotides upstream of exon 60. It does not involve a canonical ±1,2 splice site, is not a nonsense, frameshift, initiation codon, or exon deletion variant. SpliceAI predicts no significant splice impact (max delta score 0.04). No RNA evidence of aberrant splicing is available. The variant does not meet the ATM VCEP PVS1 decision tree entry criteria for a predicted or observed null variant.	spliceai pvs1_variant_assessment pvs1_gene_context vcep_atm_pvs1_1_5
PS1	Not met	PS1 is applicable only when a different nucleotide change at the same position has been established as pathogenic with the same predicted functional outcome. For intronic/splicing variants, the ATM VCEP PS1 splicing table requires a comparator P/LP reference variant at the same nucleotide or within the same donor/acceptor motif with matching predicted splice events. No such comparator variant has been identified for c.8787-26C>T, and SpliceAI predicts no splice impact (max delta 0.04), leaving no baseline prediction to match against a comparator.	spliceai vcep_atm_ps1_1_5
PS2	N/A	The ATM VCEP deems PS2 not applicable: informative de novo occurrences have not yet been observed for ATM, and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No functional data are available for NM_000051.4:c.8787-26C>T. The variant was not identified in the ATM VCEP functional assay spreadsheets (Suppl_TableS1_PMID 40580951, clingen_hbop_atm_supplementary_tables_1_and_2_v1). No literature reports variant-specific functional characterization. The variant is absent from ClinVar, COSMIC, and OncoKB. SpliceAI predicts no splicing impact (max delta 0.04), and no RNA studies have been performed.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 spliceai clinvar
PS4	Not met	The ATM VCEP requires case-control studies with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5. No case-control data are available for this variant. The variant has not been reported in ClinVar or the literature in association with disease.	cspec clinvar
PS5	N/A	PS5 is not defined in the ATM VCEP (ClinGen HBOP v1.5) framework. The VCEP criteria set does not include PS5 specifications.	cspec
PM1	N/A	The ATM VCEP deems PM1 not applicable: benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.	cspec
PM2	Not met	The ATM VCEP PM2 threshold requires allele frequency ≤0.001% in gnomAD v4. This variant has an overall allele frequency of 0.01114% (178/1,598,370 alleles) in gnomAD v4.1, which exceeds the VCEP threshold. PM2 is not met.	gnomad_v4 cspec
PM5	Not met	The ATM VCEP PM5 rule applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA) applied based on observed splicing impact. NM_000051.4:c.8787-26C>T is a deep intronic substitution, not a frameshift/truncation variant, and PVS1 is not applied. The variant type does not satisfy the VCEP PM5 rule.	cspec pm5_candidates
PM6	N/A	The ATM VCEP deems PM6 not applicable: informative de novo occurrences have not yet been observed for ATM, and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No segregation data are available for this variant. The variant has not been reported in any families or probands.	clinvar
PP2	N/A	The ATM VCEP deems PP2 not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	The ATM VCEP PP3 rule for splicing variants requires a SpliceAI delta score ≥0.2. SpliceAI predicts no significant splice impact for this variant (max delta score 0.04), which is below the VCEP threshold. PP3 is not met.	spliceai cspec
PP4	N/A	The ATM VCEP deems PP4 not applicable: for autosomal dominant disease, breast cancer has multiple genetic etiologies with no features readily distinguishing hereditary from sporadic causes; for autosomal recessive disease, such evidence is built into the A-T PM3/BP2 table.	cspec
PP5	N/A	The ATM VCEP deems PP5 not applicable for this VCEP, and the variant is absent from ClinVar with no expert panel classifications to review.	cspec clinvar
BA1	Not met	The ATM VCEP BA1 rule requires a grpmax filtering allele frequency >0.5% in gnomAD v4. The grpmax FAF for this variant is 0.0115% (0.00011482), which is well below the stand-alone benign threshold.	gnomad_v4 cspec
BS1	Not met	The ATM VCEP BS1 rule requires a grpmax filtering allele frequency >0.05% in gnomAD v4. The grpmax FAF for this variant is 0.0115% (0.00011482), which is below the strong benign threshold.	gnomad_v4 cspec
BS2	N/A	BS2 is not defined for use in the ATM VCEP (ClinGen HBOP v1.5) framework. The VCEP criteria set declares BS2 not applicable.	cspec
BS3	Not met	The ATM VCEP BS3 rule requires functional evidence that the variant rescues ATM-specific features and/or radiosensitivity. No functional studies have been performed on this variant. The variant was not identified in the VCEP functional assay spreadsheets, and no literature reports functional characterization.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec
BS4	N/A	BS4 is not defined for use in the ATM VCEP (ClinGen HBOP v1.5) framework. The VCEP criteria set declares BS4 not applicable.	cspec
BP1	N/A	The ATM VCEP deems BP1 not applicable.	cspec
BP2	Not met	No proband data are available to assess BP2. The ATM VCEP BP2 rule requires A-T proband data with trans or homozygous configuration in unaffected individuals. No such data have been reported for this variant.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	The ATM VCEP BP4 rule for splicing variants is met when SpliceAI predicts no splicing impact (delta score ≤0.1). SpliceAI max delta score for NM_000051.4:c.8787-26C>T is 0.04, which satisfies the ≤0.1 threshold. Multiple lines of computational evidence suggest no impact on splicing.	spliceai cspec
BP5	N/A	The ATM VCEP deems BP5 not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population.	cspec
BP6	N/A	The ATM VCEP deems BP6 not applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Additionally, the variant is absent from ClinVar with no benign classifications to review.	cspec clinvar
BP7	Met	The ATM VCEP BP7 rule applies to deep intronic variants located further than (but not including) -21 at the acceptor site. NM_000051.4:c.8787-26C>T is at position -26 relative to exon 60, which is beyond the -21 threshold. The variant is a deep intronic substitution with no predicted splice impact (SpliceAI max delta 0.04), consistent with a benign computational profile.	cspec spliceai
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	PM3 assessment requires A-T proband data with trans configuration. No proband data are available for this variant, and this criterion was prescreened as trivially not applicable for this case.
PM4	N/A	PM4 applies to stop-loss variants or in-frame deletions/insertions. This is a single-nucleotide intronic substitution, not a protein-length-altering variant.

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