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.1 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.2 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.3 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 0.2.4
Final classification
Likely Benign
BP4BP5BP6BP7
BRCA2
c.9234C>T
p.Val3078=
This variant
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework
Classification rationale
BP4BP5BP6BP7
Likely Benign
BRCA2 c.9234C>T
BP4 + BP5 + BP6 + BP7
→
Likely Benign
3
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗
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 · 4 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
BP4
supporting
Benign
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.
Protein position 3078 lies within BRCA2 DNA-binding region aa 2481-3186SpliceAI max delta 0.06
BP5
supporting
Benign
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.
Clinical-history LR 0.2840116366666529N_Probands 12
BP7
supporting
Benign
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.
Silent variant p.(Val3078=) / p.(V3078=)BP4 metSpliceAI max delta 0.06
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
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.
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.
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.
PS4
No case-control enrichment data or quantitative multifactorial evidence meeting ENIGMA PS4 thresholds were identified for this exact variant.
PM2
This variant is present in population databases, so the ENIGMA PM2 absence-from-controls rule is not met.
PM3
No evidence was identified for biallelic BRCA2 disease context or a quantified Fanconi-anemia-related observation that would allow PM3 assessment.
PP1
No quantitative cosegregation analysis or family-based segregation evidence meeting ENIGMA thresholds was identified for this variant.
PP3
Available computational evidence does not support a splice-disrupting effect.
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.
Benign
BA1
Population frequency does not reach the ENIGMA BA1 stand-alone benign threshold.
BS1
Population frequency does not reach the ENIGMA BS1 threshold.
BS2
No qualifying phenotype-based evidence was identified to assess BS2 under the BRCA2 Fanconi-anemia-focused ENIGMA rule.
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.
BS4
No quantitative nonsegregation evidence or benign multifactorial likelihood ratio meeting ENIGMA BS4 thresholds was identified for this exact variant.
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.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0021%
· 34 / 1,613,428
0 hom · FAF 0.002%
0 hom · FAF 0.002%
European (non-Finnish) 32 / 1,179,862 |
0.0027% |
Admixed American 1 / 59,902 |
0.0017% |
Remaining individuals 1 / 62,458 |
0.0016% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0018%
· 5 / 282,222
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
European (non-Finnish) 4 / 128,944 |
0.0031% |
Admixed American 1 / 35,282 |
0.0028% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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; COSV107498217, 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.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→BP5
supporting
Sources & reference links