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LYFE SCIENCES
Project: HERA
NM_000059.3:c.7759C>T
p.Leu2587Phe  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.73. BayesDel score = 0.147986.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL2587
Hotspots ↗