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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.

Gene
BRCA1
Transcript
NM_007294.3
HGVS · transcript:coding
NM_007294.3:c.83T>C
Consequence
N/A
GRCh38
chr17:43115777 A>G
GRCh37
chr17:41267794 A>G
Classification rationale
PM2PP3 Unclassified
BRCA1 c.83T>C

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

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 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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      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
      Not observed in any ancestry group.
      gnomAD v2.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      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)
      SpliceAI screenshot
      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 / OncoKB screenshot
      Functional Inconclusive
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      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
      21520333 ↗ LOVD v.2.0: the next generation in gene variant databases. 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
      25823446 ↗ Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR