The BRCA2 c.2818C>T (p.Gln940Ter) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations.2 This nonsense variant truncates BRCA2 at codon 940 in exon 11, where the ENIGMA BRCA2 specification assigns PVS1 and PM5_Strong (PTC) for protein-truncating variants, consistent with BRCA2 loss of function as an established disease mechanism.3 BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 from 3 probands, meeting the ENIGMA threshold for PP4_Supporting.4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, which does not reach the BRCA2 PP3 protein-impact threshold of 0.30.5
BRCA2
Final classification
Pathogenic
BRCA2 c.2818C>T · p.Gln940Ter
BRCA2
The BRCA2 c.2818C>T (p.Gln940Ter) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.
Official ClinGen ENIGMA BRCA1/BRCA2 v1.2 final-classification framework using Table 3 criteria-combination rules.
Classification rationale
PVS1PM2PM5PP4PP5
Pathogenic
BRCA2 c.2818C>T
PVS1 + PM2 + PM5 + PP4 + PP5
→
Pathogenic
3
cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextpvs1_variant_assessment
4
vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗cspec ↗
5
spliceai ↗bayesdelcspec ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 10 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
This variant is a nonsense change, NM_000059.4:c.2818C>T (p.Gln940Ter), predicted to truncate BRCA2 early in exon 11. Germline loss of function is an established BRCA2 disease mechanism, and the ENIGMA BRCA2 exon-level PVS1 table assigns exon 11 protein-truncating variants to PVS1.
p.Gln940Ter nonsense variantBRCA2 loss of function established as disease mechanismENIGMA Table 4 exon 11 PTC row = PVS1
✓
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations. Under the BRCA2 specification, absence from gnomAD supports PM2_Supporting.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
✓
PM5
strong
review
Pathogenic
In the BRCA2 ENIGMA specification, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This nonsense variant lies in exon 11, and the ENIGMA exon-level table assigns exon 11 protein-truncating variants to PM5_Strong (PTC).
Variant is a PTC/nonsense changePM5 mode is PTC gene-specificENIGMA Table 4 exon 11 PTC row = PM5_Strong (PTC)
✓
PP4
supporting
review
Pathogenic
BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands. This is above the ENIGMA PP4 supporting threshold of 2.08 and below the moderate threshold of 4.3, so PP4_Supporting is met.
Clinical-history LR = 2.535982693047889N probands = 3PP4 thresholds: Supporting >=2.08
Assessed · not applied
Pathogenic
PS3
No variant-specific calibrated functional assay result for c.2818C>T was identified in the ENIGMA BRCA1/2 functional assay table.
PS4
This variant has been reported in ClinVar and has been observed once in COSMIC, but no case-control study showing significantly increased prevalence in affected individuals with p-value 0.05 or less and odds ratio 4 or greater was identified.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 could not be assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRCA2 BA1 threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA2 BS1 supporting threshold of filter allele frequency greater than 0.002% or strong threshold greater than 0.01%.
BS2
No evidence was identified that this variant was observed in individuals without features of BRCA2-related Fanconi anemia in a manner that could be scored under the BRCA2 BS2 point system.
BS3
No variant-specific calibrated functional study showing no damaging effect was identified for c.2818C>T in the ENIGMA BRCA1/2 functional assay table.
BS4
No quantitative lack-of-segregation data were identified for this variant, so BS4 could not be assessed.
BP5
BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 for c.2818C>T based on 3 probands.
N/A · 13
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · 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
Absent from gnomAD-Canada v1.0.
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 (11 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37804)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288255.
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 previously been reported in somatic cancers (COSMIC; COSV107497862, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:17924331
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID PMID:25741868
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links
9Sources
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