LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-07
Case ID: NM_000059.3_c.8059G_T_20260507_164548
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

NM_000059.3:c.8059G>T

BRCA2  · NP_000050.2:p.(Val2687Phe)  · NM_000059.3
GRCh37: chr13:32937398 G>T  ·  GRCh38: chr13:32363261 G>T
Gene: BRCA2 Transcript: NM_000059.3
Final call
PS3_Strong PP3_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.3
Protein
NP_000050.2:p.(Val2687Phe)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
3
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.
4
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.
Final determination: PS3_Strong plus PP3_Supporting does not meet an ENIGMA BRCA1/BRCA2 Table 3 combination for Likely Pathogenic or Pathogenic classification, and no benign combination is met; therefore the variant is classified as Uncertain Significance.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Not met 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.
cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18
PS1 Not assessed 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.
cspec vcep_specifications_v1_2_2024_11_18 clinvar
PS2 N/A De novo occurrence evidence is not used in this BRCA2 ENIGMA framework because BRCA1/2-related cancers are relatively common and the predictive value of de novo occurrence has not been calibrated for these genes.
cspec vcep_specifications_v1_2_2024_11_18
PS3 Met 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.
vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 cspec
PS4 Not assessed 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.
clinvar cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1 N/A Although p.(Val2687Phe) lies within the BRCA2 DNA-binding region, the BRCA2 ENIGMA specification does not use PM1 as a standalone code and instead captures domain-based evidence within the PP3/BP4 framework.
cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2 Not assessed 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.
gnomad_v2 gnomad_v4 cspec vcep_specifications_v1_2_2024_11_18
PM3 Not assessed 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.
cspec vcep_specifications_v1_2_2024_11_18
PM4 N/A PM4 is not used in this BRCA2 ENIGMA framework and protein-length or domain-context effects are handled in the VCEP bioinformatic workflow instead.
cspec vcep_specifications_v1_2_2024_11_18
PM5 N/A In the BRCA2 ENIGMA specification, PM5 is used only for protein-termination-codon variants in eligible exons. This variant is a missense substitution and does not meet that use case.
cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6 N/A Assumed de novo occurrence evidence is not used in this BRCA2 ENIGMA framework because the predictive value of de novo occurrence has not been calibrated for BRCA1/2-related cancers.
cspec vcep_specifications_v1_2_2024_11_18
PP1 Not assessed No segregation data or quantitative co-segregation likelihood ratio was identified for this variant, so PP1 could not be applied.
cspec vcep_specifications_v1_2_2024_11_18
PP2 N/A PP2 is not used in this BRCA2 ENIGMA framework because BRCA2 has a substantial background rate of benign missense variation.
cspec vcep_specifications_v1_2_2024_11_18
PP3 Met 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.
cspec vcep_specifications_v1_2_2024_11_18 bayesdel revel spliceai vcep_appendices_v1_2_2024_11_18
PP4 Not met 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.
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec vcep_specifications_v1_2_2024_11_18
PP5 N/A PP5 is not used in this VCEP framework.
cspec vcep_specifications_v1_2_2024_11_18
BA1 Not met 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%.
gnomad_v2 gnomad_v4 cspec vcep_specifications_v1_2_2024_11_18
BS1 Not met 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%.
gnomad_v2 gnomad_v4 cspec vcep_specifications_v1_2_2024_11_18
BS2 Not assessed No calibrated BRCA2 recessive-disease or unaffected-carrier point-based evidence was identified to support BS2.
cspec vcep_specifications_v1_2_2024_11_18
BS3 Not met 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.
vcep_specifications_table9_v1_2_2024_11_18 PMID:33609447 cspec
BS4 Not assessed 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.
cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP1 Not met 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. SpliceAI is low at 0.01, but the domain criterion for BP1 is not satisfied.
cspec vcep_specifications_v1_2_2024_11_18 spliceai vcep_appendices_v1_2_2024_11_18
BP2 N/A BP2 is not used independently in this BRCA2 ENIGMA framework and is applied only in the context of BS2.
cspec vcep_specifications_v1_2_2024_11_18
BP3 N/A BP3 is not applicable in this BRCA2 ENIGMA framework.
cspec vcep_specifications_v1_2_2024_11_18
BP4 Not met 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. This does not support a benign computational interpretation.
cspec vcep_specifications_v1_2_2024_11_18 bayesdel spliceai revel
BP5 Not met 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.
vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec vcep_specifications_v1_2_2024_11_18
BP6 N/A BP6 is not used in this VCEP framework.
cspec vcep_specifications_v1_2_2024_11_18
BP7 N/A BP7 in the BRCA2 ENIGMA framework is intended for silent or intronic variants, or for RNA-only benign evidence in specific settings. This variant is a missense substitution within a clinically important domain and no benign RNA assay evidence was identified.
cspec vcep_specifications_v1_2_2024_11_18 spliceai
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