The BRCA2 c.7759C>T (p.Leu2587Phe; p.L2587F) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel classifies it as benign.1 This variant is present in gnomAD v2.1 and v4.1, with grpmax filter allele frequencies of 4.115e-05 and 4.535e-05, respectively; these values are above the ENIGMA BRCA2 BS1 Supporting threshold of 2.0e-05 and below the BS1 Strong threshold of 1.0e-04.2 In calibrated functional studies curated by the ENIGMA BRCA2 specification, this variant showed protein function similar to benign control variants, supporting BS3 at Strong strength.3 Computational evidence does not support a damaging effect under the ENIGMA BRCA2 rule because the BayesDel no-AF score is 0.147986 and the SpliceAI maximum delta score is 0.04, meeting BP4 thresholds for no predicted impact; REVEL is 0.73 but is not the operative ENIGMA BRCA2 threshold for this rule.4
BRCA2
Final classification
Likely Benign
BRCA2 c.7759C>T · p.Leu2587Phe
BRCA2
The BRCA2 c.7759C>T (p.Leu2587Phe; p.L2587F) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel classifies it as benign.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework
Classification rationale
BS1BS3BP4BP6
Likely Benign
BRCA2 c.7759C>T
BS1 + BS3 + BP4 + BP6
→
Likely Benign
2
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
3
vcep_specifications_table9_v1_2_2024_11_18
4
bayesdelspliceai ↗revelvcep_specifications_v1_2_2024_11_18
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.64705e-05; MAF= 0.00465%, 75/1613928 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00282e-05; MAF= 0.00800%, 5/62478 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.37487e-05; MAF= 0.00437%, 11/251436 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.91362e-05; MAF= 0.00791%, 9/113728 alleles, homozygotes = 0); grpmax FAF= 4.115e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0046%
· 75 / 1,613,928
0 hom · FAF 0.0045%
0 hom · FAF 0.0045%
Remaining individuals 5 / 62,478 |
0.008% |
European (non-Finnish) 67 / 1,180,010 |
0.0057% |
Admixed American 2 / 59,996 |
0.0033% |
European (Finnish) 1 / 64,016 |
0.0016% |
+ 6 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0044%
· 11 / 251,436
0 hom · FAF 0.0041%
0 hom · FAF 0.0041%
European (non-Finnish) 9 / 113,728 |
0.0079% |
Admixed American 2 / 34,590 |
0.0058% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (6 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.73. BayesDel score = 0.147986.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
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.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID vcep_appendices_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→BP4 supports · met
→BS1 supports · met
PMID vcep_specifications_table9_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID vcep_specifications_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→BP4 supports · met
→BP6 supports · met
→BS1 supports · met
Sources & reference links