Starting

Initialising…

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.

Gene

BRCA2

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.2818C>T

Consequence

N/A

GRCh38

chr13:32337173 C>T

GRCh37

chr13:32911310 C>T

Basis Official ClinGen ENIGMA BRCA1/BRCA2 v1.2 final-classification framework using Table 3 criteria-combination rules. ▾

Official ClinGen ENIGMA BRCA1/BRCA2 v1.2 final-classification framework using Table 3 criteria-combination rules.

Classification rationale

PVS1PM2PM5PP4PP5 Pathogenic

BRCA2 c.2818C>T

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

PVS1 + PM2 + PM5 + PP4 + PP5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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

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

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.288255.

SpliceAI ↗

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

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.

COSMIC ↗ Hotspots ↗

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

PMID PMID:17924331 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PP4 supports · met

PMID PMID:25741868

PMID PMID:25741868 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 supports · met

PMID PMID:31853058

PMID PMID:31853058 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PP4 supports · met

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

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