About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.9234C>T, p.(Val3078=)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BP4Supporting
BP4 · supporting
This is a silent BRCA2 variant within the DNA-binding region, and computational splicing evidence does not predict a meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1, so BP4 is met at Supporting strength.
BP5Supporting
BP5 · supporting
Clinical-history evidence is in the benign direction. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 from 12 probands, which is at or below the ENIGMA BP5 Supporting threshold of 0.48 and above the BP5 Moderate threshold of 0.23, so BP5 is met at Supporting strength.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
BP7Supporting
BP7 · supporting
This is a silent variant within a clinically important BRCA2 domain, and BP4 is met because SpliceAI predicts no significant splice impact (maximum delta score 0.06, below the 0.1 threshold). Under the ENIGMA rule for silent variants in clinically important domains, this supports BP7 at Supporting strength.
Recorded classification: Likely benign
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification 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
34 / 1,613,428 alleles
gnomAD v4.1: 34 / 1,613,428 alleles. Recorded AF 2.10731e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.77165e-05; MAF= 0.00177%, 5/282222 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10212e-05; MAF= 0.00310%, 4/128944 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
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.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
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: 4 met · 7 not met · 8 not assessed · 9 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.9234C>T (p.Val3078=; p.V3078=) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/BRCA2 expert panel.
This variant is present at low frequency in gnomAD, with AF 1.77e-05 in v2.1 and AF 2.11e-05 in v4.1; these frequencies are above the ENIGMA PM2 absence-from-controls requirement and below the BS1 and BA1 frequency thresholds.
In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 0.284 from 12 probands, which is in the benign direction and meets ENIGMA BP5 at Supporting strength.
Computational splice prediction does not support splice disruption: SpliceAI shows a maximum delta score of 0.06, below the ENIGMA BP4/BP7 threshold of 0.1 and below the PP3 splice threshold of 0.2.
No criteria match.
Met · 4
BP4 SupportingThis is a silent BRCA2 variant within the DNA-binding region, and computational splicing evidence does not predict a meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
For silent variants in clinically important BRCA2 domains, BP4 applies when SpliceAI <= 0.1.
Evidence considered
- Protein position 3078 lies within BRCA2 DNA-binding region aa 2481-3186
- SpliceAI max delta 0.06
Sources
BP5 SupportingClinical-history evidence is in the benign direction. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 from 12 probands, which is at or below the ENIGMA BP5 Supporting threshold of 0.48 and above the BP5 Moderate threshold of 0.23, so BP5 is met at Supporting strength. Details ▾Hide ▴
Rule
BP5_Supporting applies for clinical-history LR <= 0.48; BP5_Moderate requires LR <= 0.23.
Evidence considered
- Clinical-history LR 0.2840116366666529
- N_Probands 12
Sources
BP6 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign. Details ▾Hide ▴
BP7 SupportingThis is a silent variant within a clinically important BRCA2 domain, and BP4 is met because SpliceAI predicts no significant splice impact (maximum delta score 0.06, below the 0.1 threshold). Under the ENIGMA rule for silent variants in clinically important domains, this supports BP7 at Supporting strength. Details ▾Hide ▴
Rule
For silent variants in clinically important BRCA2 domains, BP7 applies at Supporting strength if BP4 is met.
Evidence considered
- Silent variant p.(Val3078=) / p.(V3078=)
- BP4 met
- SpliceAI max delta 0.06
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 This synonymous variant does not create a protein-truncating change and is not a canonical ±1,2 splice-site variant, so the BRCA2 PVS1 loss-of-function rule is not met. Details ▾Hide ▴
Rule
BRCA2 PVS1 applies to null variants or qualifying RNA evidence under the ENIGMA/ClinGen framework.
Evidence considered
- NM_000059.3:c.9234C>T encodes p.(Val3078=) / p.(V3078=)
- Generic PVS1 scaffold states this variant is outside default null-variant buckets
Sources
PM2 This variant is present in population databases, so the ENIGMA PM2 absence-from-controls rule is not met. It is seen in gnomAD v2.1 at AF 1.77e-05 (5/282222; grpmax FAF 7.02e-06) and in gnomAD v4.1 at AF 2.11e-05 (34/1613428; grpmax FAF 1.963e-05). Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from gnomAD controls with adequate coverage.
Evidence considered
- gnomAD v2.1 total AF 1.771654938310975e-05
- grpmax FAF 7.02e-06
- gnomAD v4.1 total AF 2.1073143641984645e-05
- grpmax FAF 1.963e-05
Sources
PP3 Available computational evidence does not support a splice-disrupting effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA PP3 splice threshold of 0.2. No REVEL or BayesDel score was available or relevant to support PP3 for this synonymous variant. Details ▾Hide ▴
Rule
For silent variants in BRCA2, PP3 requires predicted splicing impact with SpliceAI >= 0.2.
Evidence considered
- SpliceAI DS_AL 0.06
- all other delta scores 0.00
- max delta 0.06
Sources
PP4 The BRCA2 clinical-history likelihood ratio for this variant is 0.284 from 12 probands, which is below the ENIGMA PP4 pathogenic threshold of 2.08 and therefore does not support PP4. Details ▾Hide ▴
Rule
ENIGMA PP4 requires a clinical-history likelihood ratio >= 2.08.
Evidence considered
- Clinical-history LR 0.2840116366666529
- N_Probands 12
Sources
BA1 Population frequency does not reach the ENIGMA BA1 stand-alone benign threshold. The highest observed FAF is 1.963e-05 in gnomAD v4.1, which is well below the BA1 threshold of 0.001. Details ▾Hide ▴
Rule
BA1 requires FAF > 0.001.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.02e-06
- gnomAD v4.1 grpmax FAF 1.963e-05
Sources
BS1 Population frequency does not reach the ENIGMA BS1 threshold. The highest observed FAF is 1.963e-05 in gnomAD v4.1, which is below the BS1 Supporting threshold of 2e-05 and below the BS1 Strong threshold of 1e-04. Details ▾Hide ▴
Rule
BS1_Supporting requires FAF > 0.00002; BS1_Strong requires FAF > 0.0001.
Evidence considered
- gnomAD v2.1 grpmax FAF 7.02e-06
- gnomAD v4.1 grpmax FAF 1.963e-05
Sources
BP1 This synonymous variant is located at codon 3078, which falls within the BRCA2 DNA-binding region defined by ENIGMA as aa 2481-3186, so the outside-domain BP1 rule is not met even though no splice effect is predicted. Details ▾Hide ▴
Rule
BP1_Strong applies to silent variants outside clinically important domains with SpliceAI <= 0.1.
Evidence considered
- Protein position 3078
- ENIGMA BRCA2 DNA-binding domain aa 2481-3186
- SpliceAI max delta 0.06
Sources
Not assessed · 8 · no assessment recorded
PS1 No pathogenic or likely pathogenic reference variant with the same established splice effect was identified, so PS1 was not assessed from the available evidence. Details ▾Hide ▴
Rule
ENIGMA allows PS1 for variants with the same predicted or confirmed splice effect as a previously classified pathogenic or likely pathogenic variant.
Evidence considered
- SpliceAI max delta score 0.06
Still missing
- A curated same-splice-effect comparator variant would be needed for PS1.
Sources
PS3 This variant was not identified in the reviewed ENIGMA functional assay resources, and no calibrated damaging functional study for this exact variant was established from the available evidence. Details ▾Hide ▴
Rule
PS3 requires well-established functional evidence supporting a damaging effect.
Evidence considered
- No exact match for c.9234C>T / p.(Val3078=) was found in the reviewed ENIGMA functional assay table
Still missing
- A validated variant-specific damaging functional study would be needed for PS3.
Sources
PS4 No case-control enrichment data or quantitative multifactorial evidence meeting ENIGMA PS4 thresholds were identified for this exact variant. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals compared with controls.
Evidence considered
- No exact match for c.9234C>T / p.(Val3078=) was found in the reviewed ENIGMA posterior-probability and multifactorial tables
Still missing
- Case-control or other quantitative prevalence evidence would be needed for PS4.
Sources
PM3 No evidence was identified for biallelic BRCA2 disease context or a quantified Fanconi-anemia-related observation that would allow PM3 assessment. Details ▾Hide ▴
Rule
PM3 in BRCA2 is reserved for qualifying recessive disease observations.
Still missing
- Phenotype and phase data would be needed for PM3.
Sources
PP1 No quantitative cosegregation analysis or family-based segregation evidence meeting ENIGMA thresholds was identified for this variant. Details ▾Hide ▴
Rule
PP1 requires quantitative cosegregation evidence.
Still missing
- A quantified segregation likelihood ratio would be needed for PP1.
Sources
BS2 No qualifying phenotype-based evidence was identified to assess BS2 under the BRCA2 Fanconi-anemia-focused ENIGMA rule. Details ▾Hide ▴
Rule
BS2 in BRCA2 requires qualifying observations supporting absence of recessive disease features.
Still missing
- Qualifying recessive-disease exclusion data would be needed for BS2.
Sources
BS3 This variant was not identified in the reviewed ENIGMA functional assay resources, and no calibrated benign functional study for this exact variant was established from the available evidence. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- No exact match for c.9234C>T / p.(Val3078=) was found in the reviewed ENIGMA functional assay table
Still missing
- A validated variant-specific benign functional study would be needed for BS3.
Sources
BS4 No quantitative nonsegregation evidence or benign multifactorial likelihood ratio meeting ENIGMA BS4 thresholds was identified for this exact variant. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No exact match for c.9234C>T / p.(Val3078=) was found in the reviewed ENIGMA posterior-probability and multifactorial tables
Still missing
- A quantified nonsegregation likelihood ratio would be needed for BS4.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo occurrence criteria are not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
PM1 N/APM1 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
PM4 N/APM4 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
PM5 N/AThis is a synonymous variant and not a protein termination codon variant, so the BRCA2 PM5/PTC rule does not apply. Details ▾Hide ▴
Rule
BRCA2 PM5 in this framework is used for qualifying protein termination codon variants or qualifying missense comparators, not synonymous substitutions like this one.
Evidence considered
- Protein consequence p.(Val3078=) / p.(V3078=)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
PP5 N/APP5 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
BP2 N/ABP2 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in this BRCA2 ENIGMA framework. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.9234C>T
- Protein (HGVS p.)
- NP_000050.2:p.(Val3078=)
- GRCh38
- chr13:32380123 C>T
- GRCh37
- chr13:32954260 C>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
34 / 1,613,428 alleles
AF 2.11e-05 · 0 homozygotes · FAF 1.96e-05
gnomAD v2.1
5 / 282,222 alleles
AF 1.77e-05 · 0 homozygotes · FAF 7.02e-06
By genetic ancestry
gnomAD v4.1
AF 2.1e-05 · 34 / 1,613,428 alleles · 0 hom · FAF 2e-05
| European (non-Finnish)32 / 1,179,862 | 2.7e-05 |
| Admixed American1 / 59,902 | 1.7e-05 |
| Remaining individuals1 / 62,458 | 1.6e-05 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.8e-05 · 5 / 282,222 alleles · 0 hom · FAF 7e-06
| European (non-Finnish)4 / 128,944 | 3.1e-05 |
| Admixed American1 / 35,282 | 2.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.10731e-05; MAF= 0.00211%, 34/1613428 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.71218e-05; MAF= 0.00271%, 32/1179862 alleles, homozygotes = 0); grpmax FAF= 1.963e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.77165e-05; MAF= 0.00177%, 5/282222 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10212e-05; MAF= 0.00310%, 4/128944 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis is a silent BRCA2 variant within the DNA-binding region, and computational splicing evidence does not predict a meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
For silent variants in clinically important BRCA2 domains, BP4 applies when SpliceAI <= 0.1.
Evidence considered
- Protein position 3078 lies within BRCA2 DNA-binding region aa 2481-3186
- SpliceAI max delta 0.06
Sources
BP7 SupportingThis is a silent variant within a clinically important BRCA2 domain, and BP4 is met because SpliceAI predicts no significant splice impact (maximum delta score 0.06, below the 0.1 threshold). Under the ENIGMA rule for silent variants in clinically important domains, this supports BP7 at Supporting strength. Details ▾Hide ▴
Rule
For silent variants in clinically important BRCA2 domains, BP7 applies at Supporting strength if BP4 is met.
Evidence considered
- Silent variant p.(Val3078=) / p.(V3078=)
- BP4 met
- SpliceAI max delta 0.06
Sources
PP3 Available computational evidence does not support a splice-disrupting effect. SpliceAI shows a maximum delta score of 0.06, which is below the ENIGMA PP3 splice threshold of 0.2. No REVEL or BayesDel score was available or relevant to support PP3 for this synonymous variant. Details ▾Hide ▴
Rule
For silent variants in BRCA2, PP3 requires predicted splicing impact with SpliceAI >= 0.2.
Evidence considered
- SpliceAI DS_AL 0.06
- all other delta scores 0.00
- max delta 0.06
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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
34 / 1,613,428 recorded alleles
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/142391/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32954260-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32380123-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.9234…
- OncoKB ↗www.oncokb.org/gene/BRCA2/V3078=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123626136
- 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
This variant is present in gnomAD v4.1 (AF= 2.10731e-05; MAF= 0.00211%, 34/1613428 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.71218e-05; MAF= 0.00271%, 32/1179862 alleles, homozygotes = 0); grpmax FAF= 1.963e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.77165e-05; MAF= 0.00177%, 5/282222 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10212e-05; MAF= 0.00310%, 4/128944 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Benign 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 = 0.06).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107498217, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.