Starting
Initialising…
0%
BRCA1
Final classification
Likely Benign
BRCA1 c.670G>A · p.Ala224Thr
BRCA1

NM_007294.4:c.670G>A (p.Ala224Thr) is a missense variant in BRCA1 exon 9(10).

Gene
BRCA1
Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.670G>A
Consequence
N/A
GRCh38
chr17:43095846 C>T
GRCh37
chr17:41247863 C>T
Basis ENIGMA Table 3 point system for conflicting evidence: BP1_Strong (-4 benign points) + PM2_Supporting (+1 pathogenic point) = -3 total. Range -6 to -2 = Likely Benign.
ENIGMA Table 3 point system for conflicting evidence: BP1_Strong (-4 benign points) + PM2_Supporting (+1 pathogenic point) = -3 total. Range -6 to -2 = Likely Benign.
Classification rationale
PM2 BP1 Likely Benign
BRCA1 c.670G>A

NM_007294.4:c.670G>A (p.Ala224Thr) is a missense variant in BRCA1 exon 9(10). This variant is absent from gnomAD v2.1 and present as a singleton in gnomAD v4.1 (1/1,612,828 alleles, AF=6.2e-7), meeting PM2_Supporting under the ENIGMA BRCA1 VCEP specification v1.2.0.1 BP1_Strong is applied: the variant is a missense substitution located at amino acid position 224, which lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no splicing impact (max delta = 0.00).2 BayesDel no-AF score is 0.183, falling in the intermediate zone between BP4 (≤0.15) and PP3 (≥0.28); REVEL score is 0.541. Neither PP3 nor BP4 can be applied.3 The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 1.76 based on 1 proband, falling in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 is applicable.4 No functional assay data (PS3/BS3), case-control data (PS4), co-segregation data (PP1/BS4), or same-residue pathogenic comparator (PS1) was identified for this variant.5 Under the ENIGMA Table 3 combining rules, the evidence consists of BP1_Strong (1 strong benign) and PM2_Supporting (1 supporting pathogenic). This combination does not satisfy any Pathogenic, Likely Pathogenic, Likely Benign, or Benign classification rule. The variant is classified as a Variant of Uncertain Significance (VUS).6

PM2 + BP1 Likely Benign
3 bayesdelrevelcspec ↗
4 PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr
5 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
6 cspec ↗final_classification_framework
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
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 · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 6.20029e-07; MAF= 0.00006%, 1/1612828 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48104e-07; MAF= 0.00008%, 1/1179100 alleles, homozygotes = 0).
      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
      6.2e-05% · 1 / 1,612,828
      0 hom
      European (non-Finnish)
      1 / 1,179,100
      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
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.541. BayesDel score = 0.183223.
      Functional / OncoKB screenshot
      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. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
      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