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.1 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.2 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.3 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 PP3.4
BRCA2
Final classification
Likely Benign
BRCA2 c.9234C>T · p.Val3078=
BRCA2
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.
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules; CSPEC/VCEP override).
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 ↗
4
spliceai ↗cspec ↗vcep_specifications_v1_2_2024_11_18
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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 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
Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→BP5 supports · met
PMID cspec
Found
Structured finding pending for this record — see source link.
Applied to
→BP4 supports · met
→BP6 supports · met
→BP7 supports · met
Sources & reference links