The BRCA2 c.4516T>C (p.Phe1506Leu; p.F1506L) variant has been reported in ClinVar with conflicting classifications, including uncertain significance and likely benign submissions.1 This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (3/1,613,958 alleles; AF 0.00019%), with the highest observed frequency 1/6,062 alleles in the Middle Eastern population (AF 0.01650%).2 No variant-specific calibrated functional assay classification was identified in the reviewed BRCA2 ENIGMA functional tables, and no variant-specific reviewed functional evidence was identified in curated somatic reviewer resources.3 The substitution lies outside the BRCA2 clinically important domains defined by ENIGMA, SpliceAI predicts no significant splice effect (max delta score 0.00), and missense predictor scores are low (REVEL 0.093; BayesDel no-AF -0.650576), supporting a benign computational profile.4
BRCA2
Final classification
Uncertain Significance
BRCA2 c.4516T>C · p.Phe1506Leu
BRCA2
The BRCA2 c.4516T>C (p.Phe1506Leu; p.F1506L) variant has been reported in ClinVar with conflicting classifications, including uncertain significance and likely benign submissions.
Official ENIGMA BRCA1/BRCA2 v1.2 Table 3 final-classification framework was used. Applied evidence comprises BP1_Strong as a single strong benign criterion, with no applied pathogenic criteria. A single strong benign criterion alone does not meet ENIGMA Table 3 thresholds for Likely Benign or Benign classification, and no pathogenic classification threshold is met.
Classification rationale
BP1
Uncertain Significance
BRCA2 c.4516T>C
BP1
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
4
cspec ↗spliceai ↗revelbayesdel
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85878e-06; MAF= 0.00019%, 3/1613958 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,613,958
0 hom
0 hom
Middle Eastern 1 / 6,062 |
0.016% |
African/African American 1 / 75,040 |
0.0013% |
European (non-Finnish) 1 / 1,179,938 |
8.5e-05% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.093. BayesDel score = -0.650576.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links