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LYFE SCIENCES
Project: HERA
NM_000059.3:c.6859A>T
p.Arg2287Ter  ·  BRCA2
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Classification rationale
1

The BRCA2 c.6859A>T (p.Arg2287Ter; p.R2287*) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic with expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), consistent with extreme rarity.

gnomad_v2 ↗ gnomad_v4 ↗
3

Under the ENIGMA BRCA2 specification, this exon 12 premature termination variant is a null variant in a gene where loss of function is an established disease mechanism, and the exon-level table assigns PVS1 to protein-truncating variants in exon 12.

cspec ↗
4

SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which does not support PP3 for splice disruption.

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
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—
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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.42629e-07; MAF= 0.00006%, 1/1556108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84903e-07; MAF= 0.00009%, 1/1130068 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as likely 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: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.566539.
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.
ResidueR2287
Hotspots ↗