The BRCA2 c.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from ClinGen ENIGMA.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity, although the site-level depth information required for formal ENIGMA PM2_Supporting application was not identified here.2 In the ENIGMA BRCA2 calibrated functional dataset, p.(Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.3 This missense change lies within the BRCA2 DNA-binding domain; BayesDel no-AF is 0.377938, REVEL is 0.884, and SpliceAI max delta is 0.07, supporting a damaging protein effect without a predicted splice effect and therefore supporting PP3 but not BP4.4
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.9227G>T · p.Gly3076Val
BRCA2
The BRCA2 c.9227G>T (p.Gly3076Val) variant has not been observed in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from ClinGen ENIGMA.
ENIGMA BRCA1/2 VCEP v1.2 Table 3 combining rules applied from the official final-classification framework: 1 Strong pathogenic criterion plus 2 Supporting pathogenic criteria.
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.9227G>T
PS3 + PP3 + PP5
→
Likely Pathogenic
2
gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18
3
vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
4
cspec ↗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 · 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 · 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 Pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as 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 = 0.07). REVEL score = 0.884. BayesDel score = 0.377938.
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