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
Final classification
Likely Benign
BP1
BRCA2
c.2353A>G
p.Ile785Val
This variant
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
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_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
BP1
strong
review
Benign
This missense variant is outside the BRCA2 clinically important domains specified by ENIGMA for missense pathogenicity assessment (PALB2-binding aa 10-40; DNA-binding aa 2481-3186), and SpliceAI predicts no splice impact (max delta score 0.00). This supports BP1_Strong.
Protein change p.(Ile785Val) is outside aa 10-40 and aa 2481-3186.SpliceAI max delta score 0.00.
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PS1
No previously classified pathogenic or likely pathogenic reference variant producing the same amino acid change or the same predicted splice effect was identified in the retrieved evidence, so PS1 was not applied.
PS3
A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which does not support a damaging functional effect.
PS4
No case-control study or ENIGMA multifactorial dataset entry was identified showing a statistically significant enrichment of this variant in affected individuals compared with controls, so PS4 was not met.
PM2
This variant is present in gnomAD v2.1 with 3/282226 alleles (AF 1.06298e-05; grpmax FAF 1.082e-05), so it is not absent from controls and does not meet ENIGMA PM2_Supporting.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in a proband with BRCA2-related Fanconi anemia, so PM3 was not applied.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not applied.
PP3
This missense change is outside the BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding region (aa 2481-3186) used for ENIGMA missense PP3.
PP4
No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified, so PP4 was not applied.
Benign
BA1
The gnomAD v2.1 grpmax FAF is 1.082e-05, which is well below the ENIGMA BA1 threshold of 0.001, so BA1 is not met.
BS1
The gnomAD v2.1 grpmax FAF is 1.082e-05, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and the BS1 threshold of 0.0001, so BS1 is not met.
BS2
No point-based evidence was identified showing this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 was not applied.
BS3
A published mouse embryonic stem cell-based assay reported I785V as functionally indistinguishable from wild-type BRCA2, which is consistent with a benign effect.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied.
BP5
No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified, so BP5 was not applied.
BP7
This is a missense variant, and no RNA study showing a normal transcript outcome was identified.
N/A · 12
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6
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