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
      Population frequency
      Overall AF
      1 / 1,612,828
      6.2e-05%
      Highest · European (non-Finnish)
      8.5e-05%
      Homozygotes
      0
      Allele frequency by ancestry — gnomAD v4.1
      observed in 1 of 9 groups
      AncestryAllele countFrequencyHomozygotes
      European (non-Finnish) 1 / 1,179,100 8.5e-05% 0
      Admixed American 0 / 59,974
      European (Finnish) 0 / 63,972
      Amish 0 / 912
      East Asian 0 / 44,840
      Middle Eastern 0 / 6,058
      South Asian 0 / 90,936
      Ashkenazi Jewish 0 / 29,560
      African/African American 0 / 75,002
      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).
      Absent from gnomAD v2.1.
      This variant is absent from gnomAD-Canada.
      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