About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.8059G>T, p.(Val2687Phe)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA2 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PS3Strong
PS3 · strong
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP official framework).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 8 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
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.
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.
No criteria match.
Met · 2
PS3 StrongIn 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. Details ▾Hide ▴
Rule
Use calibrated published BRCA2 functional assay recommendations from ENIGMA Table 9.
Evidence considered
- ENIGMA Table 9 row for c.8059G>T / p.(Val2687Phe)
- Assigned code PS3 Strong
- Richardson 2021 functional result labeled damaging
Sources
PP3 SupportingThis 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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 Supporting applies to missense variants in a clinically important domain with BayesDel no-AF ≥0.30.
Evidence considered
- Protein position 2687 within BRCA2 DNA-binding domain aa2481-3186
- BayesDel no-AF 0.369316
- REVEL 0.811
- SpliceAI max delta 0.01
Sources
Not met · 8 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PVS1 applies to null variants or qualifying RNA evidence, not to a standard missense substitution without demonstrated loss-of-function transcript impact.
Evidence considered
- Missense consequence p.(Val2687Phe)
- PVS1 gene gate eligible for BRCA2 but variant not in a PVS1 default bucket
- No variant-specific RNA loss-of-function evidence identified
Sources
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP4 requires multifactorial clinical-data LR ≥2.08.
Evidence considered
- Li 2020 BRCA2 clinical-history LR row for c.8059G>T
- N_Probands 1
- LR 1.162918910256581
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗vcep_specifications_v1_2_2024_11_18
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%. Details ▾Hide ▴
Rule
BA1 requires very high population frequency above the calibrated stand-alone threshold.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
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%. Details ▾Hide ▴
Rule
BS1 requires population frequency above calibrated benign thresholds.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
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. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong rather than BS3
- Published functional result reported as damaging
Sources
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. SpliceAI is low at 0.01, but the domain criterion for BP1 is not satisfied. Details ▾Hide ▴
Rule
BP1_Strong requires missense or similar variants outside a clinically important domain with no predicted splice impact.
Evidence considered
- Protein position 2687 within DNA-binding domain aa2481-3186
- SpliceAI max delta 0.01
Sources
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. This does not support a benign computational interpretation. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 Supporting for missense variants in-domain requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.369316
- SpliceAI max delta 0.01
- REVEL 0.811
Sources
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP5 requires multifactorial clinical-data LR ≤0.48.
Evidence considered
- Li 2020 BRCA2 clinical-history LR row for c.8059G>T
- N_Probands 1
- LR 1.162918910256581
Sources
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗vcep_specifications_v1_2_2024_11_18
Not assessed · 7 · no assessment recorded
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS1 requires a previously classified pathogenic or likely pathogenic variant with the same protein effect or same proven splicing consequence.
Evidence considered
- Missense variant with low predicted splice impact
- ClinVar record reviewed but no same-amino-acid reference variant documented in the available evidence
Still missing
- A dedicated search for an alternate nucleotide change causing p.(Val2687Phe) with an established pathogenic or likely pathogenic classification would be needed to fully exclude PS1.
Sources
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PS4 requires significant enrichment in affected individuals versus controls from case-control data.
Evidence considered
- ClinVar observation record
- COSMIC somatic count 1
- No exact-variant hit found in reviewed BRCA2 posterior or multifactorial lookup tables
Still missing
- No ethnicity-matched case-control analysis was identified.
- No variant-specific odds ratio with lower confidence interval excluding 2.0 was identified.
Sources
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM2 Supporting requires absence from gnomAD v2.1 and v3.1 with adequate coverage.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Still missing
- No gnomAD v3.1-specific result was available.
- Average regional depth ≥25 was not documented.
Sources
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM3 is restricted to calibrated Fanconi anemia-related biallelic observations.
Evidence considered
- No Fanconi anemia or trans co-occurrence evidence located
Still missing
- No biallelic BRCA2 Fanconi anemia case data were identified.
- No phase-confirmed co-occurrence data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No segregation data or quantitative co-segregation likelihood ratio was identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP1 requires quantitative co-segregation evidence meeting calibrated LR thresholds.
Evidence considered
- No segregation evidence located
Still missing
- No pedigree-level segregation report was identified.
- No quantitative LR for co-segregation was identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No calibrated BRCA2 recessive-disease or unaffected-carrier point-based evidence was identified to support BS2. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS2 requires specific calibrated observations under the Table 8 framework.
Evidence considered
- No BS2 point-based evidence located
Still missing
- No Table 8 point-based evidence for absence of Fanconi anemia features was identified.
- No qualifying co-occurrence data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BS4 requires quantitative non-segregation evidence meeting calibrated LR thresholds.
Evidence considered
- No non-segregation evidence located in reviewed BRCA2 materials
Still missing
- No family-based non-segregation data were identified.
- No quantitative LR against segregation was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe 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. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Criterion listed as not applicable in BRCA2 ENIGMA specification
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM1 N/AAlthough 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. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion designated not applicable by BRCA2 ENIGMA
- Domain evidence handled through bioinformatic workflow
Sources
PM4 N/APM4 is not used in this BRCA2 ENIGMA framework and protein-length or domain-context effects are handled in the VCEP bioinformatic workflow instead. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion designated not applicable by BRCA2 ENIGMA
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 N/AIn 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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PM5 applies only to eligible protein termination codon variants.
Evidence considered
- Missense variant
- BRCA2 PM5 restricted to PTC context in Table 4
Sources
PM6 N/AAssumed 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. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Criterion listed as not applicable in BRCA2 ENIGMA specification
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP2 N/APP2 is not used in this BRCA2 ENIGMA framework because BRCA2 has a substantial background rate of benign missense variation. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion designated not applicable by BRCA2 ENIGMA
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Criterion designated not applicable by VCEP
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP2 N/ABP2 is not used independently in this BRCA2 ENIGMA framework and is applied only in the context of BS2. Details ▾Hide ▴
Rule
Not applicable in this setting.
Evidence considered
- Criterion designated not applicable except within BS2 context
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP3 N/ABP3 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Criterion designated not applicable by BRCA2 ENIGMA
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Criterion designated not applicable by VCEP
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP7 N/ABP7 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. Details ▾Hide ▴
Rule
BP7 is not applicable to this missense variant under the reviewed BRCA2 ENIGMA rules.
Evidence considered
- Missense variant in clinically important domain
- SpliceAI low but no qualifying BP7 use case
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.8059G>T
- Protein (HGVS p.)
- NP_000050.2:p.(Val2687Phe)
- GRCh38
- chr13:32363261 G>T
- GRCh37
- chr13:32937398 G>T
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.3. Select a row to find it on the plot.
BRCA2NM_000059.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis 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. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 Supporting applies to missense variants in a clinically important domain with BayesDel no-AF ≥0.30.
Evidence considered
- Protein position 2687 within BRCA2 DNA-binding domain aa2481-3186
- BayesDel no-AF 0.369316
- REVEL 0.811
- SpliceAI max delta 0.01
Sources
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. This does not support a benign computational interpretation. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 Supporting for missense variants in-domain requires BayesDel no-AF ≤0.18 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.369316
- SpliceAI max delta 0.01
- REVEL 0.811
Sources
BP7 N/ABP7 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. Details ▾Hide ▴
Rule
BP7 is not applicable to this missense variant under the reviewed BRCA2 ENIGMA rules.
Evidence considered
- Missense variant in clinically important domain
- SpliceAI low but no qualifying BP7 use case
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.811. BayesDel score = 0.369316.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535438831
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/52491/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32937398-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32363261-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.8059…
- OncoKB ↗www.oncokb.org/gene/BRCA2/V2687F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123608285
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66454617, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.