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 applied · 15 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP1
strong
Benign
This missense variant is outside the BRCA2 clinically important functional domains used by ENIGMA for missense interpretation, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, meeting BP1_Strong.
p.(Thr1586Ile) is outside aa 10-40 and aa 2481-3186 domainsSpliceAI max delta 0.01
Assessed · not applied
Pathogenic
PVS1
This missense variant does not create a premature termination codon, frameshift, or canonical ±1,2 splice-site change, so the BRCA2 PVS1 framework is not met.
PS1
No reviewed evidence was identified showing that another nucleotide change causing the same amino acid substitution has already been classified as pathogenic or likely pathogenic under the BRCA2 ENIGMA framework.
PS3
No variant-specific damaging functional study for p.(Thr1586Ile) was identified in the reviewed BRCA2 ENIGMA functional resources, so PS3 cannot be applied.
PS4
No case-control or multifactorial likelihood evidence showing enrichment of this variant in affected individuals was identified, so PS4 cannot be applied.
PM2
This variant is absent from gnomAD v2.1 and gnomAD-Canada, but it is present in gnomAD v4.1 at 1/1,613,958 alleles (AF 6.20e-07; highest population AF 8.48e-07 in European non-Finnish), so the criterion for absence from controls is not met.
PM3
No evidence was identified that this variant has been observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 cannot be applied.
PP1
No segregation likelihood ratio or family segregation dataset was identified for this variant, so PP1 cannot be applied.
PP3
Computational evidence does not support a damaging effect.
PP4
No variant-specific clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 cannot be applied.
Benign
BA1
The population frequency is far below the BA1 threshold.
BS1
The population frequency is far below the BS1 threshold.
BS2
No qualifying observation of this variant in individuals without Fanconi anemia features was identified under the BRCA2 point-based BS2 framework, so BS2 cannot be applied.
BS3
No variant-specific functional study showing normal or near-normal BRCA2 function was identified in the reviewed ENIGMA functional resources, so BS3 cannot be applied.
BS4
No quantitative non-segregation evidence was identified for this variant, so BS4 cannot be applied.
BP5
No variant-specific benign-direction clinical-history likelihood ratio was identified for this variant in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 cannot be applied.
N/A · 12
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6 · BP7
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