Starting
Initialising…
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BRCA1
Final classification
Uncertain Significance
BRCA1 c.615_622dup · p.Thr208AsnfsTer29
BRCA1

The BRCA1 c.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.

Gene
BRCA1
Transcript
NM_007294.3
HGVS · transcript:coding
NM_007294.3:c.615_622dup
Consequence
N/A
GRCh38
chr17:43095893 G>GTGATTTGT
GRCh37
chr17:41247910 G>GTGATTTGT
Basis ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (ACMG/AMP 2015 with ENIGMA Table 3 adaptations)
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (ACMG/AMP 2015 with ENIGMA Table 3 adaptations)
Classification rationale
Uncertain Significance
BRCA1 c.615_622dup

The BRCA1 c.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the available documentation was insufficient to assign BRCA1 ENIGMA PM2_Supporting under the full dataset and coverage requirements.2 Under the ENIGMA BRCA1 specification, this frameshift lies in exon 9(10), an exon designated PVS1_N/A and PM5_N/A for protein-truncating variants because rescue of an in-frame transcript is expected, so truncating status alone does not support PVS1 or PM5.3 SpliceAI shows a maximum delta score of 0.11, which is below the BRCA1 splice PP3 threshold of 0.20 and above the BP4 no-impact threshold of 0.10; however, the BRCA1 computational rules are not designed to add PP3 or BP4 evidence for this frameshift variant.4

3 cspec ↗vcep_specifications_table4_v1_2_2024_11_18
Gene diagram · NM_007294.3 · variants mapped to exon structure
BRCA1 NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 0 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.
      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.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 926510)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      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 · 9 PMIDs not cited in assessment
      11358863 ↗ Tumorigenesis in mice carrying a truncating Brca1 mutation. ONCOKB
      12483515 ↗ The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. ONCOKB
      12947386 ↗ Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. ONCOKB
      20608970 ↗ BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications. ONCOKB
      12203997 ↗ Analysis of breast cancer susceptibility genes BRCA1 and BRCA2 in Thai familial and isolated early-onset breast and ovarian cancer. CLINVAR
      16211554 ↗ Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. CLINVAR
      19892845 ↗ Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study. CLINVAR
      20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR