The BRCA2 c.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.1 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1614208 alleles; AF 6.19e-07), supporting that it is very rare in population databases.2 In a calibrated BRCA2 functional study, this variant showed protein function similar to pathogenic control variants, and the ENIGMA BRCA2 functional table assigns PS3 at strong strength for p.Thr2722Ala.3 This missense change lies within the BRCA2 DNA-binding domain, has a BayesDel no-AF score of 0.396861 above the ENIGMA PP3 threshold of 0.30, and has low predicted splice impact by SpliceAI (maximum delta score 0.01).4
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.8164A>G · p.Thr2722Ala
BRCA2
The BRCA2 c.8164A>G (p.Thr2722Ala) variant has not been observed in COSMIC and has been reported in ClinVar as Likely Pathogenic, including expert-panel review by ClinGen ENIGMA BRCA1/2.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework (CSPEC/VCEP override captured in final_classification_framework).
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.8164A>G
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18PMID:33609447 ↗cspec ↗
4
cspec ↗bayesdelspliceai ↗
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
This variant is present in gnomAD v4.1 (AF= 6.19499e-07; MAF= 0.00006%, 1/1614208 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47436e-07; MAF= 0.00008%, 1/1180030 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,208
0 hom
0 hom
European (non-Finnish) 1 / 1,180,030 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 479367)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.827. BayesDel score = 0.396861.
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