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LYFE SCIENCES
Project: HERA
NM_000059.4:c.4757C>T
p.Thr1586Ile  ·  BRCA2
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Classification rationale
1

The BRCA2 c.4757C>T (p.Thr1586Ile) variant has been reported in ClinVar as likely benign by one clinical laboratory.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present only once in gnomAD v4.1 (1/1,613,958 alleles; AF 6.20e-07), which is far below ENIGMA benign frequency thresholds but does not meet the requirement for complete absence from controls.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗ cspec ↗
3

No variant-specific functional assay result for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources.

oncokb ↗
4

Computational evidence does not support a damaging effect: p.(Thr1586Ile) lies outside the BRCA2 clinically important domains used for ENIGMA missense interpretation, SpliceAI shows a maximum delta score of 0.01, BayesDel no-AF is -0.443818, and REVEL is 0.182, supporting BP1_Strong and not supporting 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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19595e-07; MAF= 0.00006%, 1/1613958 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47515e-07; MAF= 0.00008%, 1/1179920 alleles, homozygotes = 0).
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3825379)
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 = 0.01). REVEL score = 0.182. BayesDel score = -0.443818.
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.
ResidueT1586
Hotspots ↗