Starting
Initialising…
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BRCA2
Final classification
Pathogenic
BRCA2 c.5344C>T · p.Gln1782Ter
BRCA2

NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.

Gene
BRCA2
Transcript
NM_000059.4
HGVS · transcript:coding
NM_000059.4:c.5344C>T
Consequence
N/A
GRCh38
chr13:32339699 C>T
GRCh37
chr13:32913836 C>T
Basis ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong/PTC (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) + PP5_Supporting (Supporting = 1 point) = 14 points, meeting the Pathogenic threshold (>= 10 points). Also satisfies ENIGMA Table 3 all_of Pathogenic rule: 1 Very Strong + 1 Strong (PVS1 + PM5_Strong). ▾
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong/PTC (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) + PP5_Supporting (Supporting = 1 point) = 14 points, meeting the Pathogenic threshold (>= 10 points). Also satisfies ENIGMA Table 3 all_of Pathogenic rule: 1 Very Strong + 1 Strong (PVS1 + PM5_Strong).
Classification rationale
PVS1PM2PM5PP5 Pathogenic
BRCA2 c.5344C>T

NM_000059.4:c.5344C>T (p.Gln1782Ter) is a nonsense variant in BRCA2 exon 11, creating a premature termination codon at position 1782 of 3418 amino acids. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11.1 ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in BRCA2 exon 11, where other proven pathogenic PTC variants have been established.2 The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.3 This variant has been classified as Pathogenic by the ENIGMA expert panel in ClinVar (Variation ID 51842), supported by 9 clinical laboratory submissions.4 Applying the ENIGMA Table 3 point system: PVS1 (Very Strong = 8 points) + PM5_Strong (PTC) (Strong = 4 points) + PM2_Supporting (Supporting = 1 point) = 13 points, which reaches the Pathogenic threshold (>= 10 points).5

PVS1 + PM2 + PM5 + PP5 → Pathogenic
1 vcep_specifications_table4_v1_2_2024_11_18cspec ↗
2 vcep_specifications_table4_v1_2_2024_11_18cspec ↗
3 gnomad_v2 ↗gnomad_v4 ↗cspec ↗
4 clinvar ↗
5 cspec ↗
Gene diagram · NM_000059.4 · variants mapped to exon structure
BRCA2 NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 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
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—
—
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.
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      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 Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 51842)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0368764.
      SpliceAI ↗
      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.
      COSMIC ↗ Hotspots ↗
      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
      10570174 ↗ Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations. ONCOKB
      11239455 ↗ BRCA2 is required for homology-directed repair of chromosomal breaks. ONCOKB
      20878484 ↗ A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history. ONCOKB
      22193408 ↗ BRCA1 and BRCA2: different roles in a common pathway of genome protection. ONCOKB
      24312913 ↗ A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. ONCOKB
      20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR
      23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR
      25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR