The BRCA2 c.8009C>G (p.Ser2670Trp) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls and meeting PM2_Supporting under the BRCA2 VCEP framework.2 In the BRCA2 VCEP functional assay table, this variant is recorded with splice alteration evidence including exon 18 deletion, but the reviewed evidence was not accepted for PS3 or BS3 code application, so neither functional criterion is met from the available curated data.3 For computational evidence, REVEL is 0.825, but the BRCA2 VCEP rule uses BayesDel and SpliceAI; BayesDel no-AF is 0.159332 and SpliceAI max delta score is 0.03, which supports BP4 and does not meet PP3 thresholds.4
BRCA2
Final classification
VUS
BRCA2 c.8009C>G · p.Ser2670Trp
BRCA2
The BRCA2 c.8009C>G (p.Ser2670Trp) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 with ENIGMA conflicting-evidence point system)
Classification rationale
PM2PP5
BP4
VUS
BRCA2 c.8009C>G
PM2 + PP5 + BP4
→
VUS
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
4
bayesdelspliceai ↗revelcspec ↗vcep_appendices_v1_2_2024_11_18
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 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
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 489785)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.825. BayesDel score = 0.159332.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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 · 8 PMIDs not cited in assessment
29394989 ↗
Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.
ONCOKB
16489001 ↗
Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.
ONCOKB
12228710 ↗
BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure.
CLINVAR
23108138 ↗
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
CLINVAR
24013206 ↗
A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization.
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