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
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.
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
PVS1 + PM2 + PM5 + PP5
→
Pathogenic
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 9 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000059.4:c.5344C>T is a nonsense variant (p.Gln1782Ter / p.Q1782*) in BRCA2 exon 11, creating a premature termination codon. Loss of function is the established disease mechanism for BRCA2. ENIGMA BRCA1/BRCA2 Specification v1.2 Table 4 assigns PVS1 (Very Strong) to PTC variants in exon 11. The variant is on MANE Select transcript NM_000059.4.
Nonsense substitution creating a stop codon at position 1782 in exon 11ENIGMA Table 4: PVS1 assigned to PTC variants in BRCA2 exon 11ClinVar expert panel (ENIGMA) classification: Pathogenic
✓
PM2
supporting
Pathogenic
NM_000059.4:c.5344C>T is absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Per ENIGMA PM2 rule, absence from both outbred population databases in a region with adequate read depth qualifies for PM2_Supporting.
Absent from gnomAD v2.1 (0 alleles in exomes)Absent from gnomAD v4.1 (0 alleles in exomes/genomes)
✓
PM5
strong
Pathogenic
NM_000059.4:c.5344C>T is a protein termination codon (PTC) variant in BRCA2 exon 11. ENIGMA Table 4 assigns PM5_Strong (PTC) to PTC variants in exon 11, where other proven pathogenic PTC variants have been observed. The PM5_PTC code applies additive weight to PVS1-eligible truncating variants in this exon.
ENIGMA Table 4: PM5_Strong (PTC) assigned to PTC variants in BRCA2 exon 11
Assessed · not applied
Pathogenic
PS3
ENIGMA Table 9 (curated functional assay results) covers missense and synonymous variants only.
PS4
ENIGMA PS4 requires a case-control study with p-value <= 0.05 and odds ratio >= 4 (lower confidence interval excludes 2.0).
PP1
ENIGMA PP1 requires quantitative cosegregation analysis with a Bayes score meeting specific LR thresholds (Supporting >= 2.08:1, Moderate >= 4.3:1, Strong >= 18.7:1).
PP4
ENIGMA PP4 is assessed via clinical-history likelihood ratio from Li et al.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer).
BS1
ENIGMA BS1 Strong requires FAF > 0.01% (FAF > 0.0001) in gnomAD; BS1_Supporting requires FAF > 0.002% (FAF > 0.00002).
BS2
ENIGMA BS2 is applied in the absence of Fanconi Anemia features and requires point-based scoring per proband per Specifications Table 8.
BS4
ENIGMA BS4 requires quantitative lack-of-segregation analysis with LR thresholds (Supporting <= 0.48:1, Moderate <= 0.23:1, Strong <= 0.05:1).
BP5
ENIGMA BP5 is assessed via clinical-history likelihood ratio (Li et al.
N/A · 12
PS1 · PS2 · PM1 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0368764.
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.
COSMIC
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
Triaged references · 9 PMIDs not cited in assessment
20878484 ↗
A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
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