Back
LYFE SCIENCES
Project: HERA
NM_000059.4:c.9117G>A
p.Pro3039=  ·  BRCA2
Starting
Initialising…
0%
Legacy Engine
Processing…
Classification rationale
1

The BRCA2 c.9117G>A (p.(Pro3039=), p.(P3039=)) variant has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

clinvar ↗
2

This variant is rare in population databases but is not absent from controls, with 1/248378 alleles in gnomAD v2.1 (AF 0.00000403) and 6/1613032 alleles in gnomAD v4.1 (AF 0.00000372), so PM2 is not met and BA1/BS1 thresholds are not reached.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Clinical-history likelihood-ratio analysis for BRCA2 c.9117G>A showed LR 3.91 in 12 probands, which exceeds the ENIGMA PP4 supporting threshold of 2.08 and supports PP4 at supporting strength.

PMID:31853058 ↗ cspec ↗
4

SpliceAI predicts a strong splice effect for this synonymous variant, with a maximum delta score of 0.89, which is above the ENIGMA PP3 threshold of 0.20 for predicted splicing impact and argues against BP4/BP7.

spliceai ↗ cspec ↗
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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
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= 4.02612e-06; MAF= 0.00040%, 1/248378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.95576e-06; MAF= 0.00090%, 1/111660 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.71969e-06; MAF= 0.00037%, 6/1613038 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08708e-06; MAF= 0.00051%, 6/1179458 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99061599, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP3039
Hotspots ↗