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LYFE SCIENCES
Project: HERA
NM_000059.3:c.8168A>C
p.Asp2723Ala  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In the ENIGMA BRCA2 curated functional dataset, calibrated functional studies support PS3 Strong for this variant, indicating a damaging effect on BRCA2 function.

4

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).

cspec ↗ spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.94. BayesDel score = 0.575545.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueD2723
Hotspots ↗