Starting
Initialising…
0%
BRCA1
Final classification
VUS
BRCA1 c.5073A>G · p.Thr1691=
BRCA1

NM_007294.3:c.5073A>G (p.Thr1691=) is a synonymous variant in exon 16 of BRCA1, located within the BRCT domain (aa 1650-1857), a clinically important functional domain.

Gene
BRCA1
Transcript
NM_007294.3
HGVS · transcript:coding
NM_007294.3:c.5073A>G
Consequence
N/A
GRCh38
chr17:43067609 T>C
GRCh37
chr17:41219626 T>C
Basis ENIGMA BRCA1/2 v1.2 point-based classification: PM2_Supporting (+1) + PP3_Supporting (+1) = +2 total pathogenic points. No benign criteria are met. The total of +2 falls within the ENIGMA VUS range (-1 to +5). No explicit ENIGMA Table 3 combination rule matches '2 Supporting only', and the generic ACMG/AMP 2015 rules also yield VUS (no PVS1, PS, or PM criteria are met to trigger a Pathogenic or Likely Pathogenic combination).
ENIGMA BRCA1/2 v1.2 point-based classification: PM2_Supporting (+1) + PP3_Supporting (+1) = +2 total pathogenic points. No benign criteria are met. The total of +2 falls within the ENIGMA VUS range (-1 to +5). No explicit ENIGMA Table 3 combination rule matches '2 Supporting only', and the generic ACMG/AMP 2015 rules also yield VUS (no PVS1, PS, or PM criteria are met to trigger a Pathogenic or Likely Pathogenic combination).
Classification rationale
PM2PP3 VUS
BRCA1 c.5073A>G

NM_007294.3:c.5073A>G (p.Thr1691=) is a synonymous variant in exon 16 of BRCA1, located within the BRCT domain (aa 1650-1857), a clinically important functional domain.1 The variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,607,416 alleles; AF=6.22e-7), meeting PM2_Supporting under ENIGMA population frequency criteria.2 SpliceAI predicts a donor loss effect with a max delta score of 0.71 (DS_DL=0.71), exceeding the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants, meeting PP3 at Supporting strength.3 No case-control data (PS4), cosegregation evidence (PP1), or non-segregation evidence (BS4) were identified for this variant.4 BP4 is not met because SpliceAI predicts splicing impact (0.71 > 0.1 threshold). BP1 is not applicable because the variant lies within the BRCT clinically important functional domain and has predicted splicing impact. BP7_Supporting is not met because BP4 is a prerequisite.5 No functional assay data from calibrated studies were identified in ENIGMA Table 9 or ST4. The Findlay et al. 2018 (PMID:30209399) saturation genome editing study covers this region, but the variant-specific functional score could not be retrieved from the inaccessible full-text supplementary data, leaving PS3 and BS3 unassessed.6 No clinical-history likelihood ratio data were available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 table, leaving PP4 and BP5 unassessed.7 Applying the ENIGMA point-based classification system: PM2_Supporting (+1, pathogenic) + PP3_Supporting (+1, pathogenic) = +2 total. With no benign criteria met and only two pathogenic Supporting criteria, the total points (+2) fall within the VUS range (-1 to +5).8 However, the SpliceAI prediction of donor loss (delta 0.71) suggests this synonymous variant may alter splicing, and definitive classification requires functional characterization via mRNA transcript analysis and/or retrieval of the Findlay et al. 2018 saturation genome editing functional score to resolve PS3/BS3.9

PM2 + PP3 VUS
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
      This variant is present in gnomAD v4.1 (AF= 6.22116e-07; MAF= 0.00006%, 1/1607416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51863e-07; MAF= 0.00009%, 1/1173898 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 / 1,607,416
      0 hom
      European (non-Finnish)
      1 / 1,173,898
      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 possible splice impact for this variant (max delta score = 0.71).
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
      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 · 2 PMIDs not cited in assessment
      30209399 ↗ Accurate classification of BRCA1 variants with saturation genome editing. CLINVAR
      25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR