The BRCA2 c.4757C>T (p.Thr1586Ile) variant has been reported in ClinVar as likely benign by one clinical laboratory.1 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.2 No variant-specific functional assay result for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources.3 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 PP3.4
BRCA2
Final classification
VUS
BRCA2 c.4757C>T · p.Thr1586Ile
BRCA2
The BRCA2 c.4757C>T (p.Thr1586Ile) variant has been reported in ClinVar as likely benign by one clinical laboratory.
Official BRCA2 ENIGMA/ClinGen final-classification framework using ACMG/AMP 2015 with ENIGMA Table 3 adaptations and no qualifying additional benign or pathogenic combination beyond BP1_Strong.
Classification rationale
BP1
VUS
BRCA2 c.4757C>T
BP1
→
VUS
3
vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001oncokb ↗
4
cspec ↗vcep_specifications_v1_2_2024_11_18spliceai ↗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
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,958
0 hom
0 hom
European (non-Finnish) 1 / 1,179,920 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3825379)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.182. BayesDel score = -0.443818.
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
9Sources
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR