NM_000059.4:c.8633-24T>G is an intronic variant in BRCA2 located at position -24 of intron 20. This variant is absent from gnomAD v2.1 (exomes) and v4.1 (genomes) across all populations, meeting PM2 at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0 (pending read depth confirmation at this intronic position).1 SpliceAI predicts no splicing impact (max delta score 0.00). Combined with its location outside the canonical +/-1,2 splice consensus and beyond the conserved acceptor motif (position -24, beyond -21), this meets BP4_Supporting and BP7_Supporting per ENIGMA BRCA2 VCEP v1.2.0.2 The variant is not present in ClinVar and has not been reported in the published literature. No functional assay data, case-control studies, segregation data, or clinical-history likelihood ratios are available for this specific variant.3 Per ENIGMA BRCA1 and BRCA2 VCEP Table 3 combining rules, two Supporting Benign criteria (BP4 + BP7) meet the threshold for Likely Benign. The classification is provisional pending confirmation of gnomAD read depth at position c.8633-24.4
BRCA2
Final classification
VUS
BRCA2 c.8633-24T>G · p.?
BRCA2
NM_000059.4:c.8633-24T>G is an intronic variant in BRCA2 located at position -24 of intron 20. This variant is absent from gnomAD v2.1 (exomes) and v4.1 (genomes) across all populations, meeting PM2 at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0 (pending read depth confirmation at this intronic position).
ENIGMA BRCA1/BRCA2 VCEP v1.2.0 Table 3 conflicting evidence point system: PM2 (Supporting, +1) vs BP4 (Supporting Benign, -1) + BP7 (Supporting Benign, -1). Total score = -1, which falls in the 'Uncertain Significance' range (-1 to 5). Both pathogenic and benign criteria are met, so the point system takes precedence over the non-conflicting likely_benign rule (2 Supporting Benign).
Classification rationale
PM2
BP4BP7
VUS
BRCA2 c.8633-24T>G
PM2 + BP4 + BP7
→
VUS
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
review
Pathogenic
NM_000059.4:c.8633-24T>G is absent from gnomAD v2.1 (exomes, non-cancer) and gnomAD v4.1 (genomes, non-cancer) across all populations. Per ENIGMA BRCA2 VCEP v1.2.0, PM2 is applied at Supporting strength when a variant is absent from controls in outbred populations. Read depth at this intronic position should be confirmed as ≥25x per VCEP requirements.
Absent from gnomAD v2.1 (exomesnon-cancerall populations)
✓
BP4
supporting
Benign
c.8633-24T>G is an intronic variant located outside the native donor and acceptor splice sites (position -24, beyond +/-1,2) with no predicted impact on splicing (SpliceAI max delta score 0.00, ≤0.1). BP4 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0.
Intronic variant at position -24outside canonical +/-12 splice sites
✓
BP7
supporting
Benign
c.8633-24T>G is located at intron 20 position -24, which is beyond the conserved acceptor splice motif (beyond -21). BP4 is met (SpliceAI max delta 0.00). BP7 is met at Supporting strength per ENIGMA BRCA2 VCEP v1.2.0, which applies to intronic variants outside conserved donor/acceptor motif positions when BP4 criteria are satisfied.
Position -24 is beyond the conserved acceptor splice motif (beyond -21)BP4 is metsatisfying the prerequisite for BP7_Supporting
Assessed · not applied
Pathogenic
PVS1
c.8633-24T>G is an intronic variant at position -24 of intron 20, outside the canonical donor/acceptor +/-1,2 splice consensus.
PS1
No previously classified pathogenic variant at the same nucleotide position with the same predicted splicing effect is available for comparison.
PS3
No functional assay data available for NM_000059.4:c.8633-24T>G.
PS4
No case-control study data available for this variant.
PP1
No co-segregation data available for this variant.
PP3
SpliceAI predicts no significant splicing impact (max delta score 0.00, below the ≥0.2 threshold).
PP4
The variant NM_000059.4:c.8633-24T>G is not present in the ENIGMA clinical-history likelihood ratio dataset (PMID:31853058, Li et al.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1 across all populations.
BS1
The variant is absent from gnomAD v2.1 and v4.1 across all populations.
BS2
No proband data available to assess absence of Fanconi Anemia phenotype features.
BS3
No functional assay data showing no damaging effect is available for this variant.
BS4
No co-segregation data available to assess lack of segregation in affected family members.
BP5
The variant NM_000059.4:c.8633-24T>G is not present in the ENIGMA clinical-history likelihood ratio dataset (PMID:31853058, Li et al.
N/A · 9
PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · 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 = 0.00).
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