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
Final classification
Uncertain Significance
BP1
BRCA2
c.4516T>C
p.Phe1506Leu
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BP1
strong
review
Benign
This missense variant lies outside the BRCA2 clinically important domains defined by the ENIGMA BRCA2 framework (PALB2-binding domain amino acids 10-40 and DNA-binding domain amino acids 2481-3186), and SpliceAI predicts no significant splice effect (max delta score 0.00). This meets BRCA2 BP1_Strong.
Protein change p.(Phe1506Leu) is outside aa 10-40 and aa 2481-3186.SpliceAI max delta score 0.00.
Assessed · not applied
· 4 not met · 13 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a nonsense, frameshift, canonical ±1/2 splice, or other predicted loss-of-function variant, and SpliceAI predicts no significant splice effect (max delta score 0.00).
PS1
No qualifying previously classified pathogenic or likely pathogenic variant causing the same amino acid change or the same predicted splice effect was identified from the available evidence, so PS1 was not applied.
PS3
No variant-specific calibrated functional study assignment supporting a damaging effect was identified for this variant, so PS3 was not applied.
PS4
No case-control study, odds ratio, or other qualifying evidence showing increased prevalence in affected individuals was identified for this variant, so PS4 was not applied.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 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%).
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic variant in an individual with a BRCA2-related Fanconi anemia phenotype, so PM3 was not applied.
PP1
No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied.
PP3
This missense variant lies outside the BRCA2 clinically important domains used by the ENIGMA BRCA2 framework, and SpliceAI predicts no significant splice effect (max delta score 0.00).
PP4
No exact-variant multifactorial clinical likelihood ratio meeting the ENIGMA PP4 threshold was identified, so PP4 was not applied.
Benign
BA1
This variant is present in gnomAD v4.1, but the ENIGMA BRCA2 BA1 rule is based on filter allele frequency from specified gnomAD datasets, and no qualifying BA1-level filter allele frequency was retrieved.
BS1
This variant is present in gnomAD v4.1, including 1/6,062 alleles in the Middle Eastern population (AF 0.01650%), but the ENIGMA BRCA2 BS1 rule is based on filter allele frequency from specified gnomAD datasets, and no qualifying BS1 filter allele frequency was retrieved.
BS2
No point-based evidence from unaffected or non-Fanconi anemia observations was identified for this variant, so BS2 was not applied.
BS3
No variant-specific calibrated functional study assignment showing no damaging effect was identified for this variant, so BS3 was not applied.
BS4
No quantitative non-segregation evidence or segregation likelihood ratio against pathogenicity was identified for this variant, so BS4 was not applied.
BP4
SpliceAI predicts no significant splice effect (max delta score 0.00), REVEL is low at 0.093, and BayesDel no-AF is -0.650576, consistent with a benign computational profile.
BP5
No exact-variant multifactorial clinical likelihood ratio meeting the ENIGMA BP5 threshold was identified, so BP5 was not applied.
BP7
No variant-specific RNA study showing a normal transcript outcome was identified for this missense variant, so BP7 was not applied.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
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