Starting
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BRCA1
Final classification
Likely Pathogenic
BRCA1 c.5089T>C · p.Cys1697Arg
BRCA1

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and is listed in OncoKB as Likely Oncogenic with loss-of-function effect.

Gene
BRCA1
Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.5089T>C
Consequence
N/A
GRCh38
chr17:43063937 A>G
GRCh37
chr17:41215954 A>G
Basis ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/Table 3 override) ▾
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/Table 3 override)
Classification rationale
PS3PP3PP5 Likely Pathogenic
BRCA1 c.5089T>C

The BRCA1 c.5089T>C (p.Cys1697Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and is listed in OncoKB as Likely Oncogenic with loss-of-function effect.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.2 Calibrated BRCA1 functional studies compiled by ENIGMA show complete functional impact/loss of function for p.(Cys1697Arg), supporting PS3_Strong.3 The variant lies within the BRCA1 BRCT repeat region, has a BayesDel score of 0.398 which is above the PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, supporting PP3.4

PS3 + PP3 + PP5 → Likely Pathogenic
1 clinvar ↗oncokb ↗
2 gnomad_v2 ↗gnomad_v4 ↗
3 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
4 cspec ↗vcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18spliceai ↗
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports pathogenic
      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.
      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 v4 ↗ gnomAD v2 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Likely pathogenic (6 clinical laboratories) and as Pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
      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.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots