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 synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1. This supports BP4 at supporting strength.
BP5Supporting
BP5 · supporting
Clinical-history likelihood data support a benign interpretation. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 in 12 probands, which is at or below the BP5 supporting threshold of 0.48 but above the BP5 moderate threshold of 0.23, supporting BP5 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 synonymous variant within the BRCA2 DNA-binding domain, and BP4 is met because SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, below the threshold of 0.1. Under the ENIGMA BRCA2 rule for silent variants inside a clinically important functional domain, this supports BP7 at supporting strength.
Recorded classification: Likely benign
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules; CSPEC/VCEP override).
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 oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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 · 7 not assessed · 10 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 NM_000059.4:c.9234C>T (p.Val3078=; p.V3078=) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1/2 expert panel.
This variant is rare but not absent in population databases, with gnomAD v2.1 AF 1.77165e-05 (5/282222 alleles) and gnomAD v4.1 AF 2.10731e-05 (34/1613428 alleles); the highest observed filter allele frequency is 1.963e-05, which is below the BS1 supporting threshold of greater than 0.00002 and inconsistent with the PM2 requirement for absence.
BRCA2 clinical-history likelihood data show an LR of 0.284 in 12 probands, which is at or below the BP5 supporting threshold of 0.48 and supports a benign clinical-history code.
This synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, supporting BP4 and BP7 and arguing against PP3.
No criteria match.
Met · 4
BP4 SupportingThis synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1. This supports BP4 at supporting strength. Details ▾Hide ▴
Rule
For silent variants inside a clinically important functional domain, ENIGMA BP4 applies when SpliceAI <= 0.1.
Evidence considered
- p.(Val3078=) within BRCA2 DNA-binding domain
- SpliceAI max delta score 0.06
Sources
BP5 SupportingClinical-history likelihood data support a benign interpretation. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 in 12 probands, which is at or below the BP5 supporting threshold of 0.48 but above the BP5 moderate threshold of 0.23, supporting BP5 at supporting strength. Details ▾Hide ▴
Rule
ENIGMA BP5 applies to clinical-history LR <= 0.48 for supporting strength, <= 0.23 for moderate, and <= 0.05 for strong.
Evidence considered
- clinical-history LR 0.2840116366666529
- 12 probands
Sources
BP6 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign. Details ▾Hide ▴
BP7 SupportingThis is a synonymous variant within the BRCA2 DNA-binding domain, and BP4 is met because SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, below the threshold of 0.1. Under the ENIGMA BRCA2 rule for silent variants inside a clinically important functional domain, this supports BP7 at supporting strength. Details ▾Hide ▴
Rule
For silent variants inside a clinically important functional domain, ENIGMA BP7 applies if BP4 is met.
Evidence considered
- silent variant p.(Val3078=)
- SpliceAI max delta score 0.06
- BP4 satisfied
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No evidence was identified that this variant produces the same pathogenic protein change or the same pathogenic splicing effect as a previously classified pathogenic or likely pathogenic variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is below the PP3 splicing threshold of 0.2. Details ▾Hide ▴
Rule
PS1 requires the same pathogenic amino-acid change or same pathogenic splice effect as a previously classified variant.
Evidence considered
- synonymous variant p.(Val3078=)
- SpliceAI max delta score 0.06
Sources
PM2 This variant is present in population databases and therefore does not meet the ENIGMA PM2 requirement for absence from gnomAD. It is present in gnomAD v2.1 at AF 1.77165e-05 (5/282222 alleles) and in gnomAD v4.1 at AF 2.10731e-05 (34/1613428 alleles), both with 0 homozygotes. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from gnomAD.
Evidence considered
- gnomAD v2.1 total AF 1.771654938310975e-05
- gnomAD v4.1 total AF 2.1073143641984645e-05
Sources
PP3 Computational splicing evidence does not support a deleterious effect. SpliceAI predicts a maximum delta score of 0.06, which is below the ENIGMA PP3 splicing threshold of 0.2. Details ▾Hide ▴
Rule
For silent variants, ENIGMA PP3 requires SpliceAI >= 0.2.
Evidence considered
- SpliceAI max delta score 0.06
Sources
PP4 Clinical-history likelihood data do not support pathogenicity. The BRCA2 clinical-history likelihood ratio for this variant is 0.284 in 12 probands, which is below the PP4 supporting threshold of 2.08. Details ▾Hide ▴
Rule
ENIGMA PP4 requires LR >= 2.08 for supporting strength.
Evidence considered
- clinical-history LR 0.2840116366666529
- 12 probands
Sources
BA1 Population frequency is far below the ENIGMA BA1 threshold. The highest observed filter allele frequency is 1.963e-05 in gnomAD v4.1, which is below the BA1 threshold of greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BA1 requires FAF > 0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.963e-05
- gnomAD v2.1 grpmax FAF 7.02e-06
Sources
BS1 Population frequency does not reach the ENIGMA BS1 threshold. The highest observed filter allele frequency is 1.963e-05 in gnomAD v4.1, which is below the BS1 supporting threshold of greater than 0.00002 and below the BS1 strong threshold of greater than 0.0001. Details ▾Hide ▴
Rule
ENIGMA BS1 requires FAF > 0.00002 for supporting or > 0.0001 for strong.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.963e-05
- gnomAD v2.1 grpmax FAF 7.02e-06
Sources
BP1 This synonymous variant does not meet BP1 because BRCA2 BP1_Strong for silent variants requires location outside a clinically important functional domain and no splicing prediction. Although SpliceAI is low at 0.06, codon 3078 lies within the BRCA2 DNA-binding domain (amino acids 2481-3186). Details ▾Hide ▴
Rule
ENIGMA BP1_Strong for silent variants requires location outside a clinically important functional domain and SpliceAI <= 0.1.
Evidence considered
- protein position 3078 within DNA-binding domain 2481-3186
- SpliceAI max delta score 0.06
Sources
Not assessed · 7 · no assessment recorded
PS3 No variant-specific damaging functional assay result was identified in the curated BRCA1/2 ENIGMA functional table or the reviewed BRCA multifactorial/functional supplement, so PS3 is not assessed. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence.
Evidence considered
- no direct variant match identified in curated PS3 resources
Still missing
- No variant-specific calibrated damaging functional study was identified.
Sources
PS4 No case-control study or variant-specific enrichment data were identified showing significantly increased prevalence in affected individuals, so PS4 is not assessed. Details ▾Hide ▴
Rule
PS4 requires significantly increased prevalence in affected individuals versus controls.
Evidence considered
- no variant-specific PS4 dataset identified
Still missing
- No qualifying odds ratio or case-control dataset was identified.
Sources
PM3 No evidence was identified for occurrence in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 is not assessed. Details ▾Hide ▴
Rule
PM3 in BRCA2 is reserved for qualifying Fanconi anemia observations with co-occurring variants.
Still missing
- No Fanconi anemia phenotype or in-trans data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 is not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation evidence.
Still missing
- No segregation likelihood ratio was identified.
Sources
BS2 No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for formal BS2 points assignment, so BS2 is not assessed. Details ▾Hide ▴
Rule
BS2 in BRCA2 requires point-based qualifying observations under the ENIGMA framework.
Still missing
- No BS2 point-based proband data were identified.
Sources
BS3 No variant-specific benign functional assay result was identified in the curated BRCA1/2 ENIGMA functional table or the reviewed BRCA multifactorial/functional supplement, so BS3 is not assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- no direct variant match identified in curated BS3 resources
Still missing
- No variant-specific calibrated benign functional study was identified.
Sources
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 is not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Still missing
- No segregation likelihood ratio against pathogenicity was identified.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a synonymous variant, not a nonsense, frameshift, canonical ±1,2 splice-site, initiation-codon, or exon-loss variant, so PVS1 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying RNA evidence, which are not present here.
Evidence considered
- NM_000059.4:c.9234C>T encodes p.(Val3078=)
- generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PS2 N/ADe novo occurrence is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
PM1 N/APM1 is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
PM4 N/APM4 is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
PM5 N/AThis is not a protein-terminating variant, and no alternate pathogenic amino-acid substitution framework applies to a synonymous change, so PM5 is not applicable. Details ▾Hide ▴
Rule
BRCA2 PM5 is used for qualifying protein-terminating or alternate amino-acid substitution scenarios, which are not present here.
Evidence considered
- synonymous variant p.(Val3078=)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AAssumed de novo occurrence without confirmation is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
PP2 N/APP2 is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
PP5 N/APP5 is not used in the BRCA2 ENIGMA framework. Details ▾Hide ▴
BP2 N/ABP2 is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
BP3 N/ABP3 is not an applicable BRCA2 ENIGMA criterion in this framework. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.9234C>T
- Protein (HGVS p.)
- NP_000050.3: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_000059.4. Select a row to find it on the plot.
BRCA2NM_000059.4
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 synonymous variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, which is below the ENIGMA BP4 threshold of 0.1. This supports BP4 at supporting strength. Details ▾Hide ▴
Rule
For silent variants inside a clinically important functional domain, ENIGMA BP4 applies when SpliceAI <= 0.1.
Evidence considered
- p.(Val3078=) within BRCA2 DNA-binding domain
- SpliceAI max delta score 0.06
Sources
BP7 SupportingThis is a synonymous variant within the BRCA2 DNA-binding domain, and BP4 is met because SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, below the threshold of 0.1. Under the ENIGMA BRCA2 rule for silent variants inside a clinically important functional domain, this supports BP7 at supporting strength. Details ▾Hide ▴
Rule
For silent variants inside a clinically important functional domain, ENIGMA BP7 applies if BP4 is met.
Evidence considered
- silent variant p.(Val3078=)
- SpliceAI max delta score 0.06
- BP4 satisfied
Sources
PP3 Computational splicing evidence does not support a deleterious effect. SpliceAI predicts a maximum delta score of 0.06, which is below the ENIGMA PP3 splicing threshold of 0.2. Details ▾Hide ▴
Rule
For silent variants, ENIGMA PP3 requires SpliceAI >= 0.2.
Evidence considered
- SpliceAI max delta score 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_000059.4%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 Uncertain significance (1 clinical laboratory) and as Likely Benign (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 oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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.