The BRCA2 c.8168A>C (p.Asp2723Ala, p.D2723A) variant has been reported in ClinVar and is classified as Pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.1 This variant is present at very low frequency in population databases, with 1/251098 alleles in gnomAD v2.1 (AF 3.98e-06) and 6/1614162 alleles in gnomAD v4.1 (AF 3.72e-06), which is too low to support a benign frequency criterion but means PM2 is not met because the variant is not absent from controls.2 In the ENIGMA BRCA2 curated functional dataset, calibrated functional studies support PS3 Strong for this variant, indicating a damaging effect on BRCA2 function.3 Computational evidence supports a damaging protein effect because the variant is in the BRCA2 DNA-binding region, BayesDel is 0.575545 above the PP3 threshold of 0.30, REVEL is 0.94, and SpliceAI predicts no significant splice impact (max delta score 0.00).4
BRCA2
Final classification
Likely Pathogenic
BRCA2 c.8168A>C · p.Asp2723Ala
BRCA2
The BRCA2 c.8168A>C (p.Asp2723Ala, p.D2723A) variant has been reported in ClinVar and is classified as Pathogenic by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules.
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.8168A>C
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
4
cspec ↗bayesdelrevelspliceai ↗
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= 3.7171e-06; MAF= 0.00037%, 6/1614162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08464e-06; MAF= 0.00051%, 6/1180024 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.98251e-06; MAF= 0.00040%, 1/251098 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81865e-06; MAF= 0.00088%, 1/113396 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,614,162
0 hom · FAF 0.00018%
0 hom · FAF 0.00018%
European (non-Finnish) 6 / 1,180,024 |
0.00051% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,098
0 hom
0 hom
European (non-Finnish) 1 / 113,396 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as 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 = 0.00). REVEL score = 0.94. BayesDel score = 0.575545.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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.
Sources & reference links