About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.715G>A, p.(Glu239Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen CHEK2 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
176 / 1,613,900 alleles
gnomAD v4.1: 176 / 1,613,900 alleles. Recorded AF 0.000109053. Recorded homozygote count 0.
gnomAD 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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
19 reported laboratory submissions
17 Uncertain significance · 1 Likely pathogenic · 1 uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen CHEK2 VCEP v1.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 14 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 1
PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.000084879
- gnomAD v4.1 total AF 0.000109053
- highest subpopulation AF 0.000333289
Sources
Not met · 6 · evaluated, threshold not reached
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. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
- No hotspot row found for E239
- Published domain annotation places residue in kinase domain
Sources
PP3 Computational evidence is mixed rather than consistently damaging. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.445, and BayesDel is 0.263648, so the in silico data do not clearly support a damaging computational criterion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.445
- BayesDel 0.263648
Sources
BA1 Population frequency does not reach a stand-alone benign threshold. The highest observed population frequency is 0.03333% in gnomAD v4.1 Admixed American, which is far below the 1% BA1 threshold. Details ▾Hide ▴
BS1 Population frequency is below a benign strong threshold. The highest observed population frequency is 0.03333% in gnomAD v4.1 Admixed American, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
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. Details ▾Hide ▴
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but REVEL is 0.445 and BayesDel is 0.263648, so the overall predictor profile is not clearly benign. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.445
- BayesDel 0.263648
Sources
Not assessed · 14 · no assessment recorded
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. Details ▾Hide ▴
Still missing
- A confirmed same-amino-acid pathogenic comparator was not identified.
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
No further detail was recorded.
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. However, the available evidence does not define a validated criterion strength for applying PS3 to this result alone. Details ▾Hide ▴
Evidence considered
- Published yeast-based DNA-damage response assay with intermediate score for p.E239K
Still missing
- A gene-specific or calibrated framework for converting this assay result into PS3 strength was not identified.
- No independent corroborating functional dataset for this exact variant was identified in the reviewed materials.
Sources
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. Details ▾Hide ▴
PM6 No presumed de novo occurrence without parental confirmation was identified for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 No segregation data were identified showing that this variant tracks with disease in affected relatives. Details ▾Hide ▴
No further detail was recorded.
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. Details ▾Hide ▴
No further detail was recorded.
PP4 No phenotype or family history data specific enough to support a highly specific CHEK2-related clinical presentation were identified for this variant. Details ▾Hide ▴
No further detail was recorded.
BS3 Available functional evidence does not show normal protein function. The published yeast-based DNA-damage response assay gave an intermediate score of 0.58 rather than a wild-type-like result, so BS3 is not supported. Details ▾Hide ▴
Evidence considered
- Published functional assay showed intermediate rather than normal activity
Still missing
- No independent assay showing normal function for this exact variant was identified.
Sources
BS4 No non-segregation data were identified showing that this variant fails to track with disease in a family. Details ▾Hide ▴
No further detail was recorded.
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. Details ▾Hide ▴
Evidence considered
- CHEK2 has established loss-of-function mechanism
- published CHEK2 missense functional study exists
Sources
pvs1_gene_contextPMID:22419737 ↗
BP2 No phase or co-occurrence data with another pathogenic variant were identified for this case. Details ▾Hide ▴
No further detail was recorded.
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. Details ▾Hide ▴
No further detail was recorded.
BP5 No alternate molecular explanation was identified that would account for the disease presentation independently of this variant. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense change, not a predicted null variant. Available gene-level context supports CHEK2 loss of function as a disease mechanism, but this specific c.715G>A (p.Glu239Lys, p.E239K) change does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1/2 splice variants. Details ▾Hide ▴
Evidence considered
- CHEK2 loss-of-function mechanism supported at the gene level
- variant-specific generic PVS1 scaffold indicates this missense change is outside default PVS1 buckets
Sources
pvs1_gene_contextpvs1_variant_assessment
PM3 N/APM3 is intended for recessive disorders with trans observations, which is not the relevant disease mechanism for CHEK2-related cancer predisposition in this case. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition framework is autosomal dominant
Sources
PM4 N/AThis variant is a missense substitution and does not produce a protein length change, so PM4 does not apply. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AAvailable review materials did not confirm that classic same-residue PM5 logic should be applied for this case, and no validated same-residue pathogenic comparator was established. PM5 was therefore not applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate review marked classic same-residue semantics as unconfirmed
Sources
pm5_candidates
PP5 N/APP5 is not applied because assertion-only classifications without independently reviewable evidence are not used for this interpretation. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 is not applied because assertion-only benign classifications without independently reviewable evidence are not used for this interpretation. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic variant, so BP7 does not apply. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.3
- Coding (HGVS c.)
- NM_007194.3:c.715G>A
- Protein (HGVS p.)
- NP_009125.1:p.(Glu239Lys)
- GRCh38
- chr22:28711986 C>T
- GRCh37
- chr22:29107974 C>T
- ClinVar
- 156500, 5600
Gene diagram
Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.3. Select a row to find it on the plot.
CHEK2NM_007194.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CHEK2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
176 / 1,613,900 alleles
AF 0.000109 · 0 homozygotes · FAF 0.000221
gnomAD v2.1
24 / 282,754 alleles
AF 8.49e-05 · 0 homozygotes · FAF 0.000115
By genetic ancestry
gnomAD v4.1
AF 0.00011 · 176 / 1,613,900 alleles · 0 hom · FAF 0.00022
| Admixed American20 / 60,008 | 0.00033 |
| European (Finnish)15 / 63,940 | 0.00023 |
| European (non-Finnish)134 / 1,179,920 | 0.00011 |
| Remaining individuals3 / 62,506 | 4.8e-05 |
| East Asian1 / 44,864 | 2.2e-05 |
| South Asian2 / 91,078 | 2.2e-05 |
| African/African American1 / 75,010 | 1.3e-05 |
0 alternate alleles recorded in 3 other groups: Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 8.5e-05 · 24 / 282,754 alleles · 0 hom · FAF 0.00011
| European (Finnish)8 / 25,064 | 0.00032 |
| Admixed American9 / 35,436 | 0.00025 |
| European (non-Finnish)7 / 129,138 | 5.4e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.
Statements
gnomAD 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.
gnomAD 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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.445
- BayesDel
- 0.264
How the predictions were used
PP3 Computational evidence is mixed rather than consistently damaging. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.445, and BayesDel is 0.263648, so the in silico data do not clearly support a damaging computational criterion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.445
- BayesDel 0.263648
Sources
BP4 Computational evidence does not consistently support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but REVEL is 0.445 and BayesDel is 0.263648, so the overall predictor profile is not clearly benign. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00
- REVEL 0.445
- BayesDel 0.263648
Sources
BP7 N/AThis variant is a missense substitution rather than a synonymous or intronic variant, so BP7 does not apply. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.445. BayesDel score = 0.263648.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 12533788 ↗Mutations in CHEK2 associated with prostate cancer risk.No paper-specific finding is recorded.
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PMID 16835864 ↗Characterization of CHEK2 mutations in prostate cancer.No paper-specific finding is recorded.
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PMID 22419737 ↗Response to DNA damage of CHEK2 missense mutations in familial breast cancer.Roeb W et al. · 2012No paper-specific finding is recorded.
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PMID 23298314 ↗Proteome-wide analysis of amino acid variations that influence protein lysine acetylation.No paper-specific finding is recorded.
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PMID 25525159 ↗RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.Xiong HY et al. · 2015No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 26506619 ↗Association of Germline CHEK2 Gene Variants with Risk and Prognosis of Non-Hodgkin Lymphoma.No paper-specific finding is recorded.
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PMID 28166811 ↗Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
176 / 1,613,900 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
17 Uncertain significance · 1 Likely pathogenic · 1 uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/522546466
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/5600/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29107974-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28711986-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.3%3Ac.715G…
- OncoKB ↗www.oncokb.org/gene/CHEK2/E239K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.715G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.