NM_007294.4:c.302-10_302-5delinsATTTTA is an intronic indel in BRCA1 intron 5 (legacy intron 6), spanning positions -10 to -5 relative to exon 6. SpliceAI predicts no significant splice impact (max delta score 0.01).1 This variant is absent from gnomAD v2.1 and v4.1 population databases, though intronic coverage in exome data cannot be reliably confirmed (ac=null, an=null).2 The variant has not been reported in ClinVar (0 submissions) and has not been identified in COSMIC somatic cancer databases.3 Under ENIGMA BRCA1/2 VCEP v1.2, BP4_Supporting is met: the variant is intronic, outside canonical donor/acceptor splice sites (±1,2), and SpliceAI predicts no splicing impact (max delta 0.01 ≤ 0.1).4 PVS1 is not met: the variant is an intronic indel outside the canonical splice consensus (±1,2) and does not qualify as a null variant under ENIGMA criteria. No functional or mRNA splicing data are available for PVS1_RNA.5 PM2 is not met: intronic positions lack reliable coverage depth confirmation in gnomAD exome data. PS3/BS3 are not met: no functional assay data exist for this variant in ENIGMA Table 9 or Supplementary Table 4. PP4/BP5 are not met: the variant is not listed in the Li et al. 2020 (PMID:31853058) clinical-history LR table.6 With only BP4_Supporting met, this variant is classified as a Variant of Uncertain Significance (VUS) under ENIGMA BRCA1/2 VCEP v1.2 criteria.7
BRCA1
Final classification
VUS
BRCA1 c.302-10_302-5delinsATTTTA · p.?
BRCA1
NM_007294.4:c.302-10_302-5delinsATTTTA is an intronic indel in BRCA1 intron 5 (legacy intron 6), spanning positions -10 to -5 relative to exon 6. SpliceAI predicts no significant splice impact (max delta score 0.01).
ENIGMA BRCA1/2 VCEP v1.2 Table 3 rules applied. Only one criterion is met: BP4 at supporting strength. A single supporting benign criterion does not satisfy any ENIGMA Table 3 Likely Benign combination rule (which requires at minimum 2 Supporting benign, or 1 Strong benign + 1 Supporting benign, or 1 Strong benign alone with multiple evidence types). No pathogenic criteria are met. The variant therefore defaults to Variant of Uncertain Significance (VUS).
Classification rationale
BP4
VUS
BRCA1 c.302-10_302-5delinsATTTTA
BP4
→
VUS
5
vcep_specifications_table4_v1_2_2024_11_18
6
gnomad_v2 ↗vcep_specifications_table9_v1_2_2024_11_18vcep_pmid_31853058_brca1_clinical_history_lr
7
cspec ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
Intronic variant at positions c.302-10 to c.302-5, outside the canonical donor/acceptor splice sites (±1,2). SpliceAI predicts no significant splice impact (max delta score 0.01, ≤0.1 threshold). Satisfies ENIGMA BP4_Supporting rule for intronic variants outside native splice sites with no predicted splicing impact.
SpliceAI max delta 0.01 (≤0.1)Intronic positions -10 to -5outside canonical ±1
Assessed · not applied
Pathogenic
PVS1
Intronic indel at positions c.302-10 to c.302-5, outside the canonical splice acceptor consensus (±1,2).
PS1
No previously classified pathogenic variant with the same predicted splicing impact identified at this intronic location.
PS3
No functional assay data available for this intronic indel.
PS4
No case-control data available.
PM2
Variant positions (c.302-10 to c.302-5) lie within intron 5.
PM5
ENIGMA VCEP v1.2 repurposes PM5 for protein termination codon (PTC) variants only (PM5_PTC), applicable when an exon harbors a previously proven pathogenic PTC.
PP1
No co-segregation data available.
PP3
SpliceAI max delta score 0.01, well below the ENIGMA threshold of ≥0.2 for predicted splicing impact (PP3).
PP4
Variant not present in the Li et al.
Benign
BA1
Variant absent from gnomAD v2.1 and v4.1.
BS1
Variant absent from gnomAD.
BS2
No proband observations available to assess BS2.
BS3
No well-established functional studies demonstrating no damaging effect for this intronic indel.
BS4
No segregation data available.
BP1
ENIGMA BP1 applies to coding variants (silent substitution, missense, or in-frame insertion/deletion/delins) outside clinically important functional domains with no predicted splicing impact.
BP5
Variant not present in the Li et al.
BP7
ENIGMA BP7_Supporting applies to intronic variants outside conserved acceptor motif positions (≤-21) when BP4 is met.
N/A · 9
PS2 · PM1 · PM4 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
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.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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