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LYFE SCIENCES
Project: HERA
NM_000059.4:c.2353A>G
p.Ile785Val  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ cspec ↗
3

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.

PMID:32393398 ↗ cspec ↗
4

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.

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.16. BayesDel score = -0.394429.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI785
Hotspots ↗