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.1 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.2 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.3 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.4
Final classification
VUS
PM2
CHEK2
c.715G>A
p.Glu239Lys
This variant
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.
Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
CHEK2 c.715G>A
PM2
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_007194.3 · variants mapped to exon structure
CHEK2
NM_007194.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
moderate
Pathogenic
This variant is present at low frequency in population databases. In gnomAD v2.1 the total allele frequency is 0.00849% (24/282754), and in gnomAD v4.1 it is 0.01091% (176/1613900); the highest observed subpopulation frequency is 0.03333% in Admixed American, which is below the 0.1% rarity threshold.
gnomAD v2.1 total AF 0.000084879gnomAD v4.1 total AF 0.000109053highest subpopulation AF 0.000333289
Assessed · not applied
· 6 not met · 14 not assessed
Pathogenic
PS1
No reviewed evidence was identified showing a different nucleotide change that produces the same amino acid substitution with an established pathogenic classification, so PS1 was not applied.
PS2
No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3
In a published yeast-based DNA-damage response assay, p.E239K showed an intermediate functional score of 0.58 relative to 1.00 for wild type and 0.00 for a kinase-dead control, suggesting partial loss of function.
PS4
This variant has been reported in ClinVar, but no case-control enrichment data, odds ratio, or multiple well-documented affected observations sufficient for PS4 were identified.
PM1
The variant is located in the CHEK2 kinase domain, but available evidence does not show that residue E239 is in a mutational hotspot or a well-established critical region without benign variation.
PM6
No presumed de novo occurrence without parental confirmation was identified for this variant.
PP1
No segregation data were identified showing that this variant tracks with disease in affected relatives.
PP2
Available evidence does not establish that CHEK2 is a gene in which missense variation is a sufficiently predominant mechanism with a low rate of benign missense variation to support PP2 for this variant.
PP3
Computational evidence is mixed rather than consistently damaging.
PP4
No phenotype or family history data specific enough to support a highly specific CHEK2-related clinical presentation were identified for this variant.
Benign
BA1
Population frequency does not reach a stand-alone benign threshold.
BS1
Population frequency is below a benign strong threshold.
BS2
This variant has not been observed in the homozygous state in gnomAD, and no evidence was identified showing occurrence in a number of unaffected individuals sufficient for BS2.
BS3
Available functional evidence does not show normal protein function.
BS4
No non-segregation data were identified showing that this variant fails to track with disease in a family.
BP1
Although CHEK2 loss-of-function variants are an established disease mechanism, available evidence does not justify using BP1 to discount this missense variant because damaging CHEK2 missense variants have also been reported.
BP2
No phase or co-occurrence data with another pathogenic variant were identified for this case.
BP3
No evidence was identified that this variant is located in a repetitive region or other low-complexity region where in-frame variation is commonly benign.
BP4
Computational evidence does not consistently support a benign effect.
BP5
No alternate molecular explanation was identified that would account for the disease presentation independently of this variant.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · PP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.011%
· 176 / 1,613,900
0 hom · FAF 0.022%
0 hom · FAF 0.022%
Admixed American 20 / 60,008 |
0.033% |
European (Finnish) 15 / 63,940 |
0.023% |
European (non-Finnish) 134 / 1,179,920 |
0.011% |
Remaining individuals 3 / 62,506 |
0.0048% |
East Asian 1 / 44,864 |
0.0022% |
South Asian 2 / 91,078 |
0.0022% |
African/African American 1 / 75,010 |
0.0013% |
+ 3 not observed (Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0085%
· 24 / 282,754
0 hom · FAF 0.011%
0 hom · FAF 0.011%
European (Finnish) 8 / 25,064 |
0.032% |
Admixed American 9 / 35,436 |
0.025% |
European (non-Finnish) 7 / 129,138 |
0.0054% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.445. BayesDel score = 0.263648.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
23298314 ↗
Proteome-wide analysis of amino acid variations that influence protein lysine acetylation.
CLINVAR
25525159 ↗
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
26506619 ↗
Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.
CLINVAR
28166811 ↗
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR