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LYFE SCIENCES
Project: HERA
NM_000059.4:c.2820A>G
p.Gln940=  ·  BRCA2
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Initialising…
0%
Legacy Engine
Processing…
Classification rationale
1

The BRCA2 NM_000059.4:c.2820A>G (p.(Gln940=), p.(Q940=)) variant has been reported in ClinVar as likely benign, including review by the ENIGMA expert panel and multiple clinical laboratories.

clinvar ↗
2

This variant is present at very low frequency in population databases, with 1/250640 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613806 alleles in gnomAD v4.1 (AF 0.00006%), which does not meet ENIGMA benign stand-alone or strong population thresholds and does not satisfy PM2 absence criteria.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In silico splicing analysis predicts no significant splice impact, with a SpliceAI maximum delta score of 0.00, and the synonymous p.(Gln940=) change lies outside the BRCA2 clinically important domains defined by ENIGMA, supporting BP1_Strong and arguing against PP3.

spliceai ↗ cspec ↗
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= 3.98979e-06; MAF= 0.00040%, 1/250640 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19653e-07; MAF= 0.00006%, 1/1613806 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23065e-05; MAF= 0.00223%, 1/44830 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
ResidueQ940
Hotspots ↗