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LYFE SCIENCES
Project: HERA
NM_000059.4:c.9976A>T
p.Lys3326Ter  ·  BRCA2
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Classification rationale
1

The BRCA2 c.9976A>T (p.Lys3326Ter, K3326*) variant has been observed in somatic cancers in COSMIC (18 occurrences) and has been reported in ClinVar with an expert-panel benign classification.

clinvar ↗
2

This variant is common in population databases, including gnomAD v2.1 with an overall allele frequency of 0.64680% and grpmax FAF of 0.849119%, and gnomAD v4.1 with an overall allele frequency of 0.79156%; these values are above the BRCA2 ENIGMA BA1 (>0.1%) and BS1 (>0.01%) thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Calibrated BRCA2 functional evidence supports a benign effect, with the expert specification assigning BS3 Strong to this exact variant based on protein function similar to benign controls.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07.

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= 0.00646801; MAF= 0.64680%, 1825/282158 alleles, homozygotes = 14) and has highest observed frequency in the European (Finnish) population (AF= 0.0109111; MAF= 1.09111%, 274/25112 alleles, homozygotes = 2); grpmax FAF= 0.00849119.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.00791559; MAF= 0.79156%, 12777/1614156 alleles, homozygotes = 72) and has highest observed frequency in the Amish population (AF= 0.0351648; MAF= 3.51648%, 32/910 alleles, homozygotes = 2); grpmax FAF= 0.00883986.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (30 clinical laboratories) and as Likely benign (10 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Inconclusive
OncoKB classifies this variant as Inconclusive; biological effect: Inconclusive.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66337127, n = 18 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK3326
Hotspots ↗