The BRCA2 c.8362T>C (p.Trp2788Arg, p.W2788R) variant has not been observed in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert panel classification from ClinGen ENIGMA.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting PM2 at Supporting strength.2 In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, and the BRCA2 VCEP functional evidence table assigns PS3 at Strong strength, supporting a damaging effect on BRCA2 function.3 Computational evidence supports a damaging protein effect: the variant lies in the BRCA2 DNA-binding domain, BayesDel no-AF is 0.314871, REVEL is 0.897, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03.4
Final classification
Likely Pathogenic
PS3PM2PP3PP5
BRCA2
c.8362T>C
p.Trp2788Arg
This variant
The BRCA2 c.8362T>C (p.Trp2788Arg, p.W2788R) variant has not been observed in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert panel classification from ClinGen ENIGMA.
Official ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules)
Classification rationale
PS3PM2PP3PP5
Likely Pathogenic
BRCA2 c.8362T>C
PS3 + PM2 + PP3 + PP5
→
Likely Pathogenic
2
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
3
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗
4
bayesdelrevelspliceai ↗vcep_specifications_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 · 4 applied · 13 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
In a calibrated functional study, this variant showed protein function similar to pathogenic control variants, supporting a damaging effect on BRCA2 protein function. The BRCA2 VCEP Table 9 assigns PS3 at Strong strength for c.8362T>C (p.Trp2788Arg).
Table 9 entry: BRCA2 c.8362T>C p.(Trp2788Arg) PS3 StrongRichardson 2021 functional result reported as damaging
PM2
supporting
review
Pathogenic
This variant was absent from gnomAD v2.1 and absent from gnomAD v4.1 in the reviewed population data, which is consistent with rarity in population controls and supports PM2 at Supporting strength.
gnomAD v2.1 absentgnomAD v4.1 absent
PP3
supporting
review
Pathogenic
This missense variant is located in the BRCA2 DNA-binding domain, and BayesDel no-AF is 0.314871, which is above the BRCA2 PP3 threshold of 0.30 for a damaging protein effect. REVEL is also high at 0.897. SpliceAI predicts no significant splice effect with a maximum delta score of 0.03, so the computational evidence supports a protein-level damaging interpretation rather than a splicing effect.
BayesDel no-AF 0.314871REVEL 0.897SpliceAI max delta 0.03
PP5
supporting
review
Pathogenic
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
PP5 listed as not applicable in BRCA2 VCEP rulesClinVar expert panel classification
Assessed · not applied
· 8 not met · 5 not assessed
Pathogenic
PS1
PS1 requires a previously classified variant that produces the same amino acid change.
PS4
No qualifying case-control enrichment data were identified.
PM3
No evidence was identified for occurrence with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP4
In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband.
Benign
BA1
This variant was absent from the reviewed gnomAD datasets and therefore is well below the BRCA2 BA1 threshold of filter allele frequency greater than 0.001.
BS1
This variant was absent from the reviewed gnomAD datasets and therefore does not reach the BRCA2 BS1 thresholds of filter allele frequency greater than 0.00002 or greater than 0.0001.
BS2
No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for points-based BS2 assessment, so BS2 was not assessed.
BS3
Available calibrated functional evidence supports a damaging effect rather than normal function.
BS4
No quantitative non-segregation analysis with a likelihood ratio at or below the BRCA2 BS4 thresholds was identified, so BS4 was not assessed.
BP1
BP1_Strong for BRCA2 is limited to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact.
BP4
For a missense variant in a clinically important BRCA2 domain, BP4 requires BayesDel no-AF 0.18 or lower and SpliceAI 0.1 or lower.
BP5
In the BRCA2 clinical-history likelihood-ratio table, this variant had a likelihood ratio of 1.22 based on 1 proband.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · 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.
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 Uncertain significance (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.897. BayesDel score = 0.314871.
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Strong functional data for pathogenicity or neutrality classify BRCA2 DNA-bindin
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links