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
Final classification
VUS
PM2PP5BP4
BRCA2
c.8009C>G
p.Ser2670Trp
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports rarity in population controls under the BRCA2 VCEP framework. This meets PM2 at supporting strength.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
BP4
supporting
review
Benign
This missense variant lies within the BRCA2 DNA-binding region used by the BRCA2 VCEP bioinformatic framework, and computational evidence supports no predicted impact under that rule. BayesDel no-AF is 0.159332, which is at or below the BP4 threshold of 0.18, and SpliceAI max delta score is 0.03, which is at or below the BP4 threshold of 0.1. These findings support BP4 at supporting strength.
Protein position 2670 lies within the BRCA2 DNA-binding domain 2481-3186.BayesDel no-AF score 0.159332.SpliceAI max delta score 0.03.
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PVS1
This is a missense substitution, NM_000059.3:c.8009C>G (p.Ser2670Trp), rather than a nonsense, frameshift, canonical ±1/2 splice-site, initiation-codon, or exon-level deletion/duplication variant.
PS1
No previously established pathogenic or likely pathogenic variant causing the same amino acid change or the same predicted splicing outcome was identified in the reviewed materials, so PS1 was not assessed from the available evidence.
PS3
In the BRCA2 VCEP functional table, this variant is recorded as a missense variant with splice alteration evidence, including exon 18 deletion, but the available evidence was not accepted for PS3 code application.
PS4
No case-control study or other reviewed dataset was identified showing that this variant is significantly enriched in affected individuals with an odds ratio of at least 4 and p value of 0.05 or less.
PM3
No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in a proband with phenotype consistent with BRCA2-related Fanconi anemia.
PP1
No quantitative co-segregation analysis or family likelihood ratio for this variant was identified in the reviewed materials, so PP1 was not assessed.
PP3
This missense variant lies within the BRCA2 DNA-binding region used by the BRCA2 VCEP bioinformatic framework, but the computational thresholds for PP3 are not met.
PP4
The BRCA2 clinical-history likelihood-ratio workbook did not identify an entry for this exact variant, so no variant-specific multifactorial clinical-history likelihood ratio was available to assess PP4.
Benign
BA1
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so its population frequency is well below the BA1 stand-alone benign threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so its population frequency is below the BS1 thresholds of filter allele frequency above 0.002% or 0.01%.
BS2
No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.
BS3
In the BRCA2 VCEP functional table, this variant is recorded as having splice alteration evidence, including exon 18 deletion, but the available evidence was not accepted for BS3 code application.
BS4
No quantitative non-segregation analysis or family likelihood ratio against pathogenicity was identified for this variant, so BS4 was not assessed.
BP1
This missense variant is located within the BRCA2 DNA-binding region (amino acids 2481-3186), which is treated as a clinically important functional domain in the BRCA2 VCEP framework.
BP5
The BRCA2 clinical-history likelihood-ratio workbook did not identify an entry for this exact variant, so no variant-specific multifactorial clinical-history likelihood ratio was available to assess BP5.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
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