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
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.8362T>C · p.Trp2788Arg
BRCA2
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
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 · 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.
PMID PMID:33609447
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links