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LYFE SCIENCES
Project: HERA
NM_007194.3:c.715G>A
p.Glu239Lys  ·  CHEK2
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Classification rationale
1

The CHEK2 c.715G>A (p.Glu239Lys, p.E239K) variant has been reported in ClinVar with predominantly uncertain significance submissions and one likely pathogenic submission.

clinvar ↗
2

This variant is present in gnomAD at 0.00849% in v2.1 and 0.01091% in v4.1, with a highest observed subpopulation frequency of 0.03333%, which is below the 0.1% rarity threshold and does not reach BS1 or BA1 population thresholds.

gnomad_v2 ↗ gnomad_v4 ↗
3

In a published yeast-based DNA-damage response assay, p.E239K had an intermediate score of 0.58 relative to 1.00 for wild type and 0.00 for a kinase-dead control, which is consistent with partial functional impairment but does not by itself establish a definitive functional criterion strength.

PMID:22419737 ↗
4

Computational evidence is mixed: SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.445, and BayesDel is 0.263648, so in silico evidence alone does not clearly support either a damaging or benign computational criterion.

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= 8.48794e-05; MAF= 0.00849%, 24/282754 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000319183; MAF= 0.03192%, 8/25064 alleles, homozygotes = 0); grpmax FAF= 0.00011498.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000109053; MAF= 0.01091%, 176/1613900 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000333289; MAF= 0.03333%, 20/60008 alleles, homozygotes = 0); grpmax FAF= 0.00022085.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (17 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as uncertain significance (1 clinical laboratory). (ClinVarID = 5600)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.445. BayesDel score = 0.263648.
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.
ResidueE239
Hotspots ↗