Classification rationale
BP5
VUS
No rationale recorded.
Final classification
VUS
BP5
BRCA2
c.8386C>T
p.Pro2796Ser
This variant
ENIGMA BRCA2 v1.2 Table 3 combination rules applied. Only BP5 met at Supporting benign strength (Parsons et al. 2019 combined LR=0.123). No Likely Benign combination rule matches: all Likely Benign rules require either 2x Supporting (Benign) or 1x Strong (Benign) + 1x Supporting/Moderate (Benign). No pathogenic criteria met. ENIGMA point system yields -1 point, which maps to Uncertain Significance range (-1 to 5). Variant defaults to VUS.
ENIGMA BRCA2 v1.2 Table 3 combination rules applied. Only BP5 met at Supporting benign strength (Parsons et al. 2019 combined LR=0.123). No Likely Benign combination rule matches: all Likely Benign rules require either 2x Supporting (Benign) or 1x Strong (Benign) + 1x Supporting/Moderate (Benign). No pathogenic criteria met. ENIGMA point system yields -1 point, which maps to Uncertain Significance range (-1 to 5). Variant defaults to VUS.
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
BP5
supporting
Benign
ENIGMA BP5 Supporting applies when the combined likelihood ratio from multifactorial likelihood clinical data is ≤ 0.48:1. The combined LR from Parsons et al. 2019 (PMID:31131967) multifactorial analysis for NM_000059.4:c.8386C>T is 0.123, with a posterior probability of pathogenicity of 0.0038 and IARC class 2 (Likely Benign). The combined LR of 0.123 supports BP5 at Supporting strength. The combined LR incorporates co-occurrence, family history, pathology, and case-control likelihood components.
ENIGMA BP5 Supporting: combined LR ≤ 0.48Parsons et al. 2019 SuppT1: Combined LR = 0.123 (≤ 0.48 → BP5 Supporting)Posterior probability of pathogenicity: 0.0038
Assessed · not applied
· 11 not met · 4 not assessed
Pathogenic
PS1
No previously classified pathogenic missense variant at codon 2796 has been identified.
PS3
NM_000059.4:c.8386C>T is not listed in ENIGMA Specifications Table 9 (curated BRCA2 functional assay results).
PS4
No case-control data meeting ENIGMA PS4 thresholds (p ≤ 0.05 and OR ≥ 4) are available for this variant.
PM2
Under ENIGMA BRCA2 v1.2, PM2 (Supporting only) requires absence from controls in gnomAD outbred populations.
PP1
No co-segregation data are available for quantitative analysis.
PP3
Although p.Pro2796Ser lies within the BRCA2 DNA binding domain (aa 2481-3186), neither ENIGMA PP3 condition is satisfied: BayesDel no-AF score is -0.202329 (threshold ≥ 0.30 not met) and SpliceAI max delta is 0.16 (threshold ≥ 0.2 not met).
PP4
ENIGMA PP4 requires a combined LR ≥ 2.08:1 toward pathogenicity from multifactorial likelihood clinical data.
Benign
BA1
ENIGMA BA1 (Stand Alone) requires filter allele frequency (FAF) > 0.1% (0.001) in gnomAD.
BS1
ENIGMA BS1 Strong requires FAF > 0.01% (0.0001); BS1 Supporting requires FAF > 0.002% (0.00002).
BS2
ENIGMA BS2 requires proband-level assessment for absence of Fanconi Anemia phenotype features, scored per Specifications Table 8.
BS3
NM_000059.4:c.8386C>T is not listed in ENIGMA Specifications Table 9 (curated functional assay results).
BS4
ENIGMA BS4 requires a quantitative co-segregation analysis with LR ≤ 0.48:1 toward benign.
BP1
ENIGMA BP1 Strong requires a missense variant located OUTSIDE a clinically important functional domain AND no splicing predicted (SpliceAI ≤ 0.1).
BP4
ENIGMA BP4 requires BOTH BayesDel no-AF ≤ 0.18 AND SpliceAI ≤ 0.1 for missense variants inside a clinically important functional domain.
BP7
ENIGMA BP7 Strong (RNA) for missense variants inside a clinically important functional domain requires BS3 to be met first.
N/A · 12
PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.73486e-05; MAF= 0.00173%, 28/1613960 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 5.33163e-05; MAF= 0.00533%, 4/75024 alleles, homozygotes = 0); grpmax FAF= 1.744e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.59082e-05; MAF= 0.00159%, 4/251442 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51716e-05; MAF= 0.00352%, 4/113728 alleles, homozygotes = 0); grpmax FAF= 1.122e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0017%
· 28 / 1,613,960
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
African/African American 4 / 75,024 |
0.0053% |
European (non-Finnish) 24 / 1,179,856 |
0.002% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0016%
· 4 / 251,442
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
European (non-Finnish) 4 / 113,728 |
0.0035% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 91511)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.16). REVEL score = 0.328. BayesDel score = -0.202329.
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 · 9 PMIDs not cited in assessment
22505045 ↗
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
24094589 ↗
A clinically validated diagnostic second-generation sequencing assay for detection of hereditary BRCA1 and BRCA2 mutations.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
30254663 ↗
Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help?
CLINVAR
30263092 ↗
Rapid detection of copy number variations and point mutations in BRCA1/2 genes using a single workflow by ion semiconductor sequencing pipeline.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR