The BRCA2 c.8168A>C (p.Asp2723Ala; p.D2723A) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel and is listed by OncoKB as likely oncogenic.1 This variant is present at very low frequency in population databases, with 1/251098 alleles in gnomAD v2.1 and 6/1614162 alleles in gnomAD v4.1, which is too low to support benign frequency criteria but means PM2 is not met because the variant is not absent from controls.2 Calibrated BRCA2 functional evidence supports a damaging effect, and the ENIGMA curated functional table assigns PS3 at Strong strength for p.Asp2723Ala.3 This missense change occurs within the BRCA2 DNA-binding domain, SpliceAI predicts no splice disruption with a max delta score of 0.00, and the computational profile supports PP3 rather than BP4.4
Final classification
Likely Pathogenic
PS3PP3PP5
BRCA2
c.8168A>C
p.Asp2723Ala
This variant
The BRCA2 c.8168A>C (p.Asp2723Ala; p.D2723A) variant has been reported in ClinVar as pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel and is listed by OncoKB as likely oncogenic.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via final_classification_framework).
Classification rationale
PS3PP3PP5
Likely Pathogenic
BRCA2 c.8168A>C
PS3 + PP3 + PP5
→
Likely Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
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Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 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
Pathogenic
Calibrated functional studies summarized by the ENIGMA BRCA2 specification show that this variant has damaging protein function consistent with pathogenic control variants, and the curated ENIGMA functional table assigns PS3 at Strong strength.
Specifications Table 9 entry: BRCA2 c.8168A>C p.(Asp2723Ala) -> PS3 Strong.Table 9 summary states the variant was reported by two calibrated studies to exhibit protein function similar to pathogenic control variants.
PP3
supporting
Pathogenic
This missense variant lies within the BRCA2 DNA-binding domain, a clinically important functional domain (aa 2481-3186), and the BayesDel no-AF score is 0.575545, which is above the ENIGMA PP3 threshold of 0.30. SpliceAI predicts no splice effect (max delta score 0.00), so the supporting computational evidence is for protein impact rather than splicing.
Protein change: p.(Asp2723Ala)located within BRCA2 DNA-binding domain aa 2481-3186.BayesDel no-AF score: 0.575545.
Assessed · not applied
· 9 not met · 5 not assessed
Pathogenic
PS1
No previously classified pathogenic or likely pathogenic variant producing the same amino acid change was identified.
PS4
No qualifying variant-specific case-control study or odds ratio meeting ENIGMA PS4 thresholds was identified.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed in trans with another BRCA2 variant in an individual with a BRCA2-related Fanconi anemia phenotype, so PM3 could not be assessed.
PP1
No quantitative co-segregation likelihood ratio was identified, so PP1 could not be assessed.
PP4
Variant-specific clinical-history evidence falls in the neutral zone.
Benign
BA1
The population frequency is far below the ENIGMA BA1 threshold.
BS1
The population frequency does not reach the ENIGMA BS1 threshold.
BS2
No proband-level evidence was identified to assign BS2 points under the BRCA2 Fanconi anemia framework, so BS2 could not be assessed.
BS3
Available functional evidence does not support a benign effect.
BS4
No quantitative lack-of-segregation likelihood ratio was identified, so BS4 could not be assessed.
BP1
This missense variant is located within the BRCA2 DNA-binding domain, whereas BRCA2 BP1_Strong is reserved for missense or silent variants outside a clinically important functional domain with no splice effect.
BP4
Although SpliceAI predicts no splice effect (max delta score 0.00), BP4 is not met because this missense variant is in a clinically important functional domain and the BayesDel no-AF score is 0.575545, which is above the ENIGMA benign threshold of 0.18 rather than at or below it.
BP5
Variant-specific clinical-history evidence does not support a benign multifactorial signal.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
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 classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
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