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LYFE SCIENCES
Project: HERA
NM_000059.3:c.8164A>G
p.Thr2722Ala  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:33609447 ↗ cspec ↗
4

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).

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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.827. BayesDel score = 0.396861.
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.
ResidueT2722
Hotspots ↗