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
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA2
c.9227G>T
p.Gly3076Val
This variant
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
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 · 16 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
PS3
strong
review
Pathogenic
In the ENIGMA BRCA2 calibrated functional dataset, c.9227G>T (p.Gly3076Val) showed abnormal function similar to pathogenic control variants, supporting PS3 at strong strength.
Table 9 row for BRCA2 c.9227G>T p.(Gly3076Val): PS3 Strong.Functional summary states the variant was damaging in one calibrated study.
PP3
supporting
review
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186). BayesDel no-AF is 0.377938, which is above the ENIGMA PP3 threshold of 0.30, REVEL is 0.884, and SpliceAI predicts no significant splice effect (max delta 0.07), supporting a damaging protein effect consistent with PP3.
Protein change p.(Gly3076Val) is within the BRCA2 DNA-binding domain.BayesDel no-AF score = 0.377938.REVEL score = 0.884.
Assessed · not applied
· 9 not met · 7 not assessed
Pathogenic
PVS1
This variant is a missense substitution, not a nonsense, frameshift, initiation-loss, or canonical ±1,2 splice variant.
PS1
No previously classified variant with the same proven amino-acid change or the same demonstrated splice effect was identified here, so PS1 could not be assessed from the available evidence.
PS4
This variant has been reported in ClinVar, but no case-control study, odds ratio, or other quantitative prevalence evidence meeting the ENIGMA PS4 rule was identified here.
PM2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 could not be assessed.
PP1
No segregation data were identified for this variant, so PP1 could not be assessed.
PP4
The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is below the ENIGMA PP4 supporting threshold of 2.08.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%.
BS2
No qualifying observations in individuals without features of BRCA2-related Fanconi anemia were identified for the ENIGMA BS2 point-based rule, so BS2 could not be assessed.
BS3
Available calibrated functional evidence showed an abnormal damaging effect rather than normal function, so BS3 is not supported for this variant.
BS4
No non-segregation data with a quantitative likelihood ratio were identified for this variant, so BS4 could not be assessed.
BP1
This missense variant lies within the BRCA2 DNA-binding domain (amino acids 2481-3186), so it does not meet the ENIGMA BP1 rule, which is limited to missense or silent changes outside clinically important functional domains with no predicted splice effect.
BP4
Although SpliceAI predicts no significant splice effect (max delta 0.07, below the BP4 threshold of 0.1), BayesDel no-AF is 0.377938, which is above the benign BP4 threshold of 0.18.
BP5
The BRCA2 clinical-history likelihood ratio for c.9227G>T is 0.776 with 1 proband, which is above the ENIGMA BP5 supporting threshold of 0.48.
BP7
This is a missense variant within a clinically important BRCA2 functional domain, and no RNA evidence showing a benign transcript effect was identified.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
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 33609447
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links