The BRCA2 NM_000059.4:c.2353A>G (p.(Ile785Val), p.(I785V)) variant has been reported in ClinVar, with predominantly uncertain significance submissions and one likely benign submission.1 This variant is present in gnomAD v2.1 at AF 1.06298e-05 (3/282226 alleles) with grpmax FAF 1.082e-05, which is below ENIGMA BA1 and BS1 thresholds and also means the variant is not absent from controls for PM2.2 In a published mouse embryonic stem cell-based assay, I785V was reported as functionally indistinguishable from wild-type BRCA2; however, this variant was not identified with a preassigned PS3 or BS3 code in the ENIGMA curated functional table, so the functional evidence remains for manual review.3 This missense change lies outside the BRCA2 PALB2-binding and DNA-binding domains used for ENIGMA missense pathogenicity assessment, SpliceAI predicts no splice impact (max delta 0.00), BayesDel is -0.394429, and REVEL is 0.16, supporting BP1_Strong and arguing against PP3.4
BRCA2
Final classification
Likely Benign
BRCA2 c.2353A>G · p.Ile785Val
BRCA2
The BRCA2 NM_000059.4:c.2353A>G (p.(Ile785Val), p.(I785V)) variant has been reported in ClinVar, with predominantly uncertain significance submissions and one likely benign submission.
Official ENIGMA BRCA1/BRCA2 v1.2 Table 3 final-classification framework was used. The only applied criterion is BP1_Strong, and the framework permits a Likely Benign classification from one strong benign criterion when that code reflects multiple evidence types.
Classification rationale
BP1
Likely Benign
BRCA2 c.2353A>G
BP1
→
Likely Benign
3
PMID:32393398 ↗vcep_specifications_table9_v1_2_2024_11_18cspec ↗
4
cspec ↗spliceai ↗bayesdelrevel
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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= 1.17725e-05; MAF= 0.00118%, 19/1613924 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000186637; MAF= 0.01866%, 17/91086 alleles, homozygotes = 0); grpmax FAF= 0.00011837.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.06298e-05; MAF= 0.00106%, 3/282226 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000139159; MAF= 0.01392%, 1/7186 alleles, homozygotes = 0); grpmax FAF= 1.082e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0012%
· 19 / 1,613,924
0 hom · FAF 0.012%
0 hom · FAF 0.012%
South Asian 17 / 91,086 |
0.019% |
Remaining individuals 1 / 62,484 |
0.0016% |
European (non-Finnish) 1 / 1,179,960 |
8.5e-05% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0011%
· 3 / 282,226
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
Remaining individuals 1 / 7,186 |
0.014% |
South Asian 2 / 30,610 |
0.0065% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.16. BayesDel score = -0.394429.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links