NM_000051.4:c.8419-7T>G is located 7 bases upstream of the exon 58 acceptor site in ATM and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_Supporting).1 SpliceAI predicts a strong splicing impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), meeting the ATM VCEP PP3_Supporting threshold for intronic variants outside canonical splice sites (PP3_Supporting).2 The variant is outside the canonical +/-1,2 splice acceptor consensus, and no RNA-based evidence of aberrant splicing is available; PVS1 is therefore not met under the ATM VCEP PVS1 decision tree.3 No functional studies, segregation data, case-control data, or variant-specific literature are available. ClinVar classifies this variant as Uncertain significance (1 submitter, ClinVarID 3325300).4
ATM
Final classification
VUS
ATM c.8419-7T>G · p.?
ATM
NM_000051.4:c.8419-7T>G is located 7 bases upstream of the exon 58 acceptor site in ATM and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2_Supporting).
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
ATM c.8419-7T>G
PM2 + PP3
→
VUS
3
vcep_atm_pvs1_1_5pvs1_variant_assessment
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000051.4:c.8419-7T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0%), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% in gnomAD v4.
Absent from gnomAD v2.1 (AF = 0.0%)Absent from gnomAD v4.1 (AF = 0.0%)Absent from gnomAD-Canada v1.0 (AF = 0.0%)
✓
PP3
supporting
Pathogenic
SpliceAI predicts a strong splice impact with a maximum delta score of 0.90 (DS_AL=0.90, DS_AG=0.86), exceeding the ATM VCEP PP3_Supporting threshold of ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites. PP3 for splice predictions is applied independently here as PVS1 is not met. The variant is located 7 bases upstream of the exon 58 acceptor site, where SpliceAI predicts acceptor loss.
SpliceAI max delta score = 0.90 (≥0.2 threshold met)DS_AL = 0.90 (acceptor loss)DS_AG = 0.86 (acceptor gain)
Assessed · not applied
Pathogenic
PVS1
Variant is located at c.8419-7 (7 bases upstream of exon 58 acceptor site), which is outside the canonical +/-1,2 splice acceptor consensus.
PS1
Per the ATM VCEP PS1 Splicing table, for variants located outside the donor/acceptor +/-1,2 dinucleotide positions the baseline predictive code is PP3.
PS3
No variant-specific functional studies are available.
PS4
No case-control studies or proband enrichment data are available for this variant.
PP1
No segregation data are available for this variant.
Benign
BA1
The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BA1 Stand Alone threshold of >0.5%.
BS1
The variant is absent from gnomAD v4.1 (grpmax filtering AF = 0.0%), which does not meet the ATM VCEP BS1 Strong threshold of >0.05%.
BS3
No functional studies demonstrating rescue of ATM-specific features or radiosensitivity are available.
BP2
No proband data are available to score against the ATM PM3/BP2 table.
BP4
SpliceAI predicts strong splice impact (max delta = 0.90), far exceeding the ATM VCEP BP4 Supporting threshold of ≤0.1 for benign splicing prediction.
N/A · 16
PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3325300)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.90).
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
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR