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LYFE SCIENCES
Project: HERA
NM_000059.4:c.2818C>T
p.Gln940Ter  ·  BRCA2
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Legacy Engine
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Classification rationale
1

The BRCA2 c.2818C>T (p.Gln940Ter) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in reference populations.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
3

This nonsense variant truncates BRCA2 at codon 940 in exon 11, where the ENIGMA BRCA2 specification assigns PVS1 and PM5_Strong (PTC) for protein-truncating variants, consistent with BRCA2 loss of function as an established disease mechanism.

cspec ↗
4

BRCA2 clinical-history likelihood analysis reported a likelihood ratio of 2.54 from 3 probands, meeting the ENIGMA threshold for PP4_Supporting.

PMID:31853058 ↗ cspec ↗
5

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the BayesDel no-AF score is 0.288, which does not reach the BRCA2 PP3 protein-impact threshold of 0.30.

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
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 37804)
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 = 0.00). BayesDel score = 0.288255.
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; COSV107497862, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ940
Hotspots ↗