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LYFE SCIENCES
Project: HERA
NM_000059.4:c.2830A>T
p.Lys944Ter  ·  BRCA2
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Legacy Engine
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Classification rationale
1

The BRCA2 c.2830A>T (p.Lys944Ter; p.K944*) variant has been reported in ClinVar as pathogenic by an expert panel and is classified by OncoKB as likely oncogenic with likely loss of function.

clinvar ↗ oncokb ↗
2

This variant is present at very low frequency in gnomAD, with AF 1.06375e-05 (3/282020 alleles) in v2.1 and AF 3.71824e-06 (6/1613668 alleles) in v4.1, which is below ENIGMA BRCA2 BS1 and BA1 thresholds but means PM2 is not met because the variant is not absent from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This nonsense variant occurs in BRCA2 exon 11, a PVS1-eligible exon in the ENIGMA BRCA2 specification, and exon 11 protein termination codon variants are assigned PM5_Strong (PTC), supporting a loss-of-function interpretation.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.

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
—
—
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= 1.06375e-05; MAF= 0.00106%, 3/282020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.02123e-05; MAF= 0.00402%, 1/24868 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.71824e-06; MAF= 0.00037%, 6/1613668 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33461e-05; MAF= 0.00133%, 1/74928 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (37 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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 previously been reported in somatic cancers (COSMIC; COSV66450359, n = 4 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueK944
Hotspots ↗