NM_007294.3:c.83T>C (p.Leu28Pro) is a missense variant in BRCA1 exon 3, located within the RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications.1 This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.2 In silico analysis predicts a deleterious effect: BayesDel no-AF score of 0.451556 exceeds the ENIGMA PP3 threshold of 0.28 for predicted damaging protein impact, and REVEL score is 0.832. SpliceAI predicts no splicing impact (max delta 0.00). These findings meet ENIGMA PP3 at Supporting strength.3 BP4 is not met because the BayesDel score (0.451556) exceeds the ENIGMA benign prediction threshold of 0.15.4 The variant is classified as Uncertain Significance (VUS) in ClinVar by the ENIGMA expert panel (ClinVar ID 55732), with 6 clinical laboratories reporting VUS and 1 reporting Likely Pathogenic.5 Functional evidence (PS3/BS3) could not be assessed: ENIGMA Table 9 does not list c.83T>C, OncoKB classifies the effect as Inconclusive, and no publication abstract confirmed variant-specific functional data. The variant lies within the RING domain targeted by saturation genome editing studies (Findlay 2018, Starita 2015) but full-text verification is needed.6 Clinical evidence (PP4/BP5 via Li et al. 2020 clinical history LR; PP1/BS4 via cosegregation) could not be assessed due to unavailability of variant-level data in the extracted materials.7
BRCA1
Final classification
Unclassified
BRCA1 c.83T>C · p.Leu28Pro
BRCA1
NM_007294.3:c.83T>C (p.Leu28Pro) is a missense variant in BRCA1 exon 3, located within the RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications.
Classification rationale
PM2PP3
Unclassified
BRCA1 c.83T>C
PM2 + PP3
→
Unclassified
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting requirement: absent from controls in an outbred population in both gnomAD non-cancer subsets.
Absent from gnomAD v2.1 exome non-cancerabsent from gnomAD v4.1 non-cancer.
✓
PP3
supporting
Pathogenic
The variant is a missense substitution (p.Leu28Pro) located within the BRCA1 RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.451556, which exceeds the ENIGMA PP3 threshold of ≥0.28 for predicted deleterious protein impact. SpliceAI max delta is 0.00, consistent with a protein-change mechanism rather than splicing. REVEL score of 0.832 provides additional in silico support.
BayesDel no-AF = 0.451556 (≥0.28 threshold)REVEL = 0.832SpliceAI max delta = 0.00
Assessed · not applied
Pathogenic
PS1
No previously classified pathogenic missense variant has been identified at BRCA1 codon 28.
PS3
ENIGMA Table 9 (curated functional assay results) does not list c.83T>C.
PS4
No case-control study demonstrating significantly increased prevalence in affected individuals (p≤0.05, OR≥4) has been identified for this variant.
PP1
No cosegregation data identified for this variant.
PP4
ENIGMA PP4 requires multifactorial likelihood clinical data with LR ≥2.08 (Supporting).
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1.
BS1
The variant is absent from gnomAD v2.1 and v4.1.
BS2
ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia features.
BS3
ENIGMA Table 9 does not list a pre-assigned BS3 code for c.83T>C.
BS4
No segregation data demonstrating lack of cosegregation in affected family members has been identified for this variant.
BP4
ENIGMA BP4 for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1.
BP5
ENIGMA BP5 requires multifactorial likelihood clinical data supporting benignity (LR ≤0.48 for Supporting).
N/A · 12
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 Uncertain significance (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 55732)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.832. BayesDel score = 0.451556.
Functional
Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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
Triaged references · 8 PMIDs not cited in assessment
16403807 ↗
Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility.
ONCOKB
22034435 ↗
BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.
ONCOKB
15235020 ↗
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR