The BRCA2 c.8059G>T (p.Val2687Phe, p.V2687F) variant has been observed in somatic cancer once in COSMIC (COSV66454617) and has been reported in ClinVar with an ENIGMA expert-panel classification of uncertain significance alongside mixed clinical-laboratory submissions.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.2 In a published calibrated BRCA2 functional study, p.(Val2687Phe) showed protein function similar to pathogenic control variants, and the ENIGMA BRCA2 functional table assigns PS3 at Strong strength for this damaging result.3 Computational data support a damaging protein effect, with BayesDel no-AF 0.369316 above the BRCA2 ENIGMA PP3 threshold of 0.30 and REVEL 0.811, while SpliceAI is low at 0.01 and does not suggest a meaningful splice effect.4
Final classification
Uncertain Significance
PS3PP3
BRCA2
c.8059G>T
p.Val2687Phe
This variant
The BRCA2 c.8059G>T (p.Val2687Phe, p.V2687F) variant has been observed in somatic cancer once in COSMIC (COSV66454617) and has been reported in ClinVar with an ENIGMA expert-panel classification of uncertain significance alongside mixed clinical-laboratory submissions.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP official framework).
Classification rationale
PS3PP3
Uncertain Significance
BRCA2 c.8059G>T
PS3 + PP3
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗
4
bayesdelrevelspliceai ↗cspec ↗vcep_specifications_v1_2_2024_11_18
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_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
Pathogenic
In a calibrated published functional study, c.8059G>T (p.Val2687Phe) showed protein function similar to pathogenic control variants, consistent with a damaging effect on BRCA2 function; the BRCA2 ENIGMA functional table assigns PS3 at Strong strength for this variant.
ENIGMA Table 9 row for c.8059G>T / p.(Val2687Phe)Assigned code PS3 StrongRichardson 2021 functional result labeled damaging
PP3
supporting
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain encompassed by the ENIGMA computational framework, and the BayesDel no-AF score is 0.369316, which is above the PP3 threshold of 0.30. REVEL is also elevated at 0.811, while SpliceAI is low at 0.01, supporting a predicted damaging protein effect rather than a splice-driven effect.
Protein position 2687 within BRCA2 DNA-binding domain aa2481-3186BayesDel no-AF 0.369316REVEL 0.811
Assessed · not applied
· 8 not met · 7 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.(Val2687Phe), rather than a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level loss-of-function variant, and no RNA evidence was identified showing an abnormal transcript effect that would justify PVS1 under the BRCA2 ENIGMA framework.
PS1
No previously classified pathogenic or likely pathogenic BRCA2 variant producing the same amino-acid change was identified in the available evidence, so PS1 could not be established from the reviewed materials.
PS4
The variant has been observed in ClinVar submissions and once in COSMIC, but no case-control study, odds ratio, or calibrated case-enrichment dataset meeting BRCA2 ENIGMA PS4 requirements was identified.
PM2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity, but the BRCA2 ENIGMA PM2 rule specifically calls for absence in gnomAD v2.1 and v3.1 with average regional depth at least 25, and a v3.1-specific result and depth confirmation were not available here.
PM3
No evidence was identified that this variant occurred in trans with another BRCA2 pathogenic or likely pathogenic variant in an individual with BRCA2-related Fanconi anemia, so PM3 could not be applied.
PP1
No segregation data or quantitative co-segregation likelihood ratio was identified for this variant, so PP1 could not be applied.
PP4
Variant-specific clinical-history likelihood data showed LR 1.1629 in 1 proband, which is below the BRCA2 ENIGMA PP4 threshold of 2.08, so this evidence does not support PP4.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the BRCA2 ENIGMA BA1 stand-alone frequency threshold of FAF greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BRCA2 ENIGMA BS1 frequency thresholds of FAF above 0.002% or 0.01%.
BS2
No calibrated BRCA2 recessive-disease or unaffected-carrier point-based evidence was identified to support BS2.
BS3
Available calibrated functional evidence does not show normal BRCA2 function for this variant; instead, the reviewed ENIGMA functional table assigns a damaging result supporting PS3, so BS3 is not met.
BS4
No quantitative non-segregation likelihood ratio or pedigree evidence showing failure to track with disease was identified for this variant, so BS4 could not be applied.
BP1
The variant affects codon 2687 within the BRCA2 DNA-binding domain, so it is not outside a clinically important functional domain and does not meet the BP1_Strong requirement.
BP4
Although SpliceAI is low at 0.01, the BayesDel no-AF score is 0.369316, which is above the BRCA2 ENIGMA BP4 threshold of 0.18 or less.
BP5
Variant-specific clinical-history likelihood data showed LR 1.1629 in 1 proband, which is above the BRCA2 ENIGMA BP5 threshold of 0.48 or less, so this evidence does not support BP5.
N/A · 11
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 pathogenic (2 clinical laboratories) and as Uncertain Significance 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 = 0.01). REVEL score = 0.811. BayesDel score = 0.369316.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66454617, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-bindin
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links