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).1 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.2 BP4 (supporting) is applied per the ATM VCEP v1.5: SpliceAI predicts no splicing impact (max delta 0.04 ≤ 0.1 threshold).3 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.4 The variant is absent from ClinVar, COSMIC, and the published literature. No functional studies, segregation data, or case-control studies are available.5 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).6
ATM
Final classification
Likely Benign
ATM c.8787-26C>T · p.?
ATM
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).
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: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
BP4BP7
Likely Benign
ATM c.8787-26C>T
BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
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 max delta score 0.04VCEP BP4 splicing threshold: ≤0.1 — satisfied
✓
BP7
supporting
Benign
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.
Variant is at intronic position -26beyond the VCEP BP7 cutoff of -21SpliceAI max delta 0.04
Assessed · not applied
Pathogenic
PVS1
NM_000051.4:c.8787-26C>T is a deep intronic variant located 26 nucleotides upstream of exon 60.
PS1
PS1 is applicable only when a different nucleotide change at the same position has been established as pathogenic with the same predicted functional outcome.
PS3
No functional data are available for NM_000051.4:c.8787-26C>T.
PS4
The ATM VCEP requires case-control studies with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.
PM2
The ATM VCEP PM2 threshold requires allele frequency ≤0.001% in gnomAD v4.
PM5
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.
PP1
No segregation data are available for this variant.
PP3
The ATM VCEP PP3 rule for splicing variants requires a SpliceAI delta score ≥0.2.
Benign
BA1
The ATM VCEP BA1 rule requires a grpmax filtering allele frequency >0.5% in gnomAD v4.
BS1
The ATM VCEP BS1 rule requires a grpmax filtering allele frequency >0.05% in gnomAD v4.
BS3
The ATM VCEP BS3 rule requires functional evidence that the variant rescues ATM-specific features and/or radiosensitivity.
BP2
No proband data are available to assess BP2.
N/A · 14
PS2 · PM1 · PM3 · PM4 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000111363; MAF= 0.01114%, 178/1598370 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000132081; MAF= 0.01321%, 154/1165954 alleles, homozygotes = 0); grpmax FAF= 0.00011482.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.01302e-05; MAF= 0.00601%, 17/282720 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138619; MAF= 0.01386%, 1/7214 alleles, homozygotes = 0); grpmax FAF= 4.442e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.011%
· 178 / 1,598,370
0 hom · FAF 0.011%
0 hom · FAF 0.011%
European (non-Finnish) 154 / 1,165,954 |
0.013% |
South Asian 10 / 90,750 |
0.011% |
Remaining individuals 6 / 61,950 |
0.0097% |
Admixed American 5 / 59,982 |
0.0083% |
African/African American 2 / 74,516 |
0.0027% |
East Asian 1 / 44,788 |
0.0022% |
+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.006%
· 17 / 282,720
0 hom · FAF 0.0044%
0 hom · FAF 0.0044%
Remaining individuals 1 / 7,214 |
0.014% |
South Asian 4 / 30,614 |
0.013% |
European (non-Finnish) 9 / 129,092 |
0.007% |
Admixed American 2 / 35,436 |
0.0056% |
African/African American 1 / 24,970 |
0.004% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links