About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.906A>C, p.(Glu302Asp)
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
PM2Supporting
PM2 · supporting
This variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 0.00342% (8/234112), and in gnomAD v4.1 the total allele frequency is 0.00097% (14/1437854) with highest observed subpopulation frequency 0.03471% (2/5762) in Middle Eastern individuals; these values are below the 0.1% rarity threshold, supporting PM2 at a supporting level.
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 supporting; combination = 1 supporting, 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
14 / 1,437,854 alleles
gnomAD v4.1: 14 / 1,437,854 alleles. Recorded AF 9.73673e-06. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.41717e-05; MAF= 0.00342%, 8/234112 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.68494e-05; MAF= 0.00668%, 2/29918 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 9 not met · 12 not assessed · 6 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.906A>C (p.Glu302Asp, p.E302D) variant has not been observed in COSMIC and has been reported in ClinVar as a variant of uncertain significance.
This variant is present at low frequency in population databases, with gnomAD v2.1 total allele frequency 0.00342% (8/234112) and gnomAD v4.1 total allele frequency 0.00097% (14/1437854); the highest observed subpopulation frequency is 0.03471% (2/5762) in Middle Eastern individuals, which remains below a 0.1% rarity threshold.
In silico data do not show a consistent damaging signal: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, REVEL is 0.41, and BayesDel is 0.0235302.
No criteria match.
Met · 1
PM2 SupportingThis variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 0.00342% (8/234112), and in gnomAD v4.1 the total allele frequency is 0.00097% (14/1437854) with highest observed subpopulation frequency 0.03471% (2/5762) in Middle Eastern individuals; these values are below the 0.1% rarity threshold, supporting PM2 at a supporting level. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 3.417e-05
- gnomAD v4.1 total AF 9.737e-06
- Highest subpopulation AF 3.471e-04
Still missing
- Gene-specific frequency thresholds were not available in the retrieved CHEK2 rule set.
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No alternate nucleotide change producing the same p.(Glu302Asp) amino acid substitution with an established pathogenic classification was identified in ClinVar, so PS1 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar exact variant review
- No established pathogenic same-amino-acid alternative identified
Still missing
- A broader expert-curated residue-level review could be performed if additional same-amino-acid submissions emerge.
Sources
PM1 Available evidence does not show that residue 302 lies in a statistically significant hotspot or a well-established critical region without benign variation, so PM1 is not met. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review found no hotspot row for CHEK2 E302
Still missing
- A codon-level expert hotspot curation was not available.
Sources
PM5 Other codon 302 missense changes were identified in ClinVar, but they are reported as uncertain significance or conflicting rather than established pathogenic variants, so PM5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar codon 302 review showed VUS/conflicting nearby missense variants
Still missing
- A residue-level expert panel review could be revisited if a pathogenic codon 302 missense variant is established later.
Sources
PP3 Available computational evidence does not support a damaging prediction. SpliceAI shows no significant predicted splice effect with a maximum delta score of 0.01, REVEL is 0.41, and BayesDel is 0.0235302; taken together, these results do not reach a consistent damaging threshold for PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.41
- BayesDel 0.0235302
Still missing
- No CHEK2-specific computational calibration rule was available in the retrieved rule set.
Sources
BA1 Population frequency does not meet the benign stand-alone threshold. The highest observed frequency is 0.03471% in gnomAD v4.1 Middle Eastern individuals, which is well below 1%. Details ▾Hide ▴
BS1 Population frequency is below the benign strong threshold. The highest observed frequency is 0.03471% in gnomAD v4.1, which is below the 0.3% threshold, so BS1 is not met. Details ▾Hide ▴
BS2 One homozygote is present in gnomAD v4.1, but no phenotype data are available for that individual, and this alone is not sufficient to establish observation in healthy adults for CHEK2-related cancer predisposition. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 reports 1 homozygote
- CHEK2-related cancer predisposition is autosomal dominant
Still missing
- Phenotypic confirmation of unaffected status is not available.
Sources
BP1 Although loss of function is an established CHEK2 disease mechanism, missense variants have also been functionally implicated in CHEK2, so a missense change alone does not support BP1. Details ▾Hide ▴
Evidence considered
- CHEK2 loss-of-function mechanism supported
- CHEK2 missense variants can be functionally important
Sources
pvs1_gene_contextPMID:37449874 ↗
BP4 Available computational evidence does not provide a consistent benign prediction. SpliceAI predicts no significant splice effect, but REVEL is 0.41 and BayesDel is 0.0235302, which together do not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.41
- BayesDel 0.0235302
Still missing
- No CHEK2-specific benign computational calibration rule was available in the retrieved rule set.
Sources
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Published trio or family-based de novo data were not identified.
Sources
PS3 Published CHEK2 functional studies were identified in the literature set, but an exact validated abnormal functional result for p.(Glu302Asp) was not confirmed from the available evidence, so PS3 is not applied. Details ▾Hide ▴
Evidence considered
- CHEK2 functional literature identified
- No verified exact variant-specific abnormal result confirmed
Still missing
- Direct review of exact variant-level assay data from the cited functional studies is still needed.
Sources
PS4 This variant has been reported in ClinVar, but no variant-specific case-control enrichment data or exact odds ratio demonstrating increased prevalence in affected individuals were identified. Details ▾Hide ▴
Evidence considered
- ClinVar VUS submissions
- Population frequencies in gnomAD
Still missing
- Variant-specific case counts and control comparison data were not identified.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Published family-based occurrence data were not identified.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Family segregation studies were not identified.
Sources
PP2 Available evidence shows that missense variants can be relevant in CHEK2, but the retrieved evidence does not establish a gene-level missense mechanism or missense constraint basis sufficient to apply PP2 for this variant. Details ▾Hide ▴
Evidence considered
- CHEK2 missense functional literature identified
- No explicit CHEK2 PP2 rule available
Still missing
- A gene-level missense constraint or VCEP-specific PP2 rule was not available in the retrieved materials.
Sources
PP4 No phenotype information specific enough to support a highly CHEK2-specific clinical presentation was provided. Details ▾Hide ▴
Evidence considered
- Gene-disease context reviewed
Still missing
- Detailed personal and family phenotype data would be needed.
Sources
BS3 Published CHEK2 functional studies were identified, but an exact validated normal functional result for p.(Glu302Asp) was not confirmed from the available evidence, so BS3 is not applied. Details ▾Hide ▴
Evidence considered
- CHEK2 functional literature identified
- No verified exact variant-specific normal result confirmed
Still missing
- Direct review of exact variant-level assay data from the cited functional studies is still needed.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Family studies demonstrating lack of segregation were not identified.
Sources
BP2 No evidence was identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant condition, or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Phase and co-occurrence data were not identified.
Sources
BP3 No evidence was identified that this variant lies in a repetitive region or a region without known function that would support BP3. Details ▾Hide ▴
Evidence considered
- No hotspot or special regional annotation identified
Still missing
- Region-specific repeat or low-complexity annotation was not available in the retrieved evidence.
Sources
BP5 No alternate molecular diagnosis or clearly independent cause for disease was identified. Details ▾Hide ▴
Evidence considered
- ClinVar summary review
Still missing
- Detailed phenotype and broader genotype context were not available.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution, p.(Glu302Asp), and it does not fall in a nonsense, frameshift, or canonical +/-1,2 splice category for which PVS1 is typically considered. Details ▾Hide ▴
Evidence considered
- Missense consequence p.Glu302Asp
- Generic PVS1 scaffold did not place this variant in a null-variant bucket
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/APM3 is a recessive trans-with-pathogenic criterion, whereas the retrieved CHEK2 disease context is autosomal dominant cancer predisposition. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition listed with autosomal dominant inheritance
Sources
PM4 N/AThis variant is a missense substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense consequence without in-frame indel or stop-loss
Sources
pvs1_variant_assessment
PP5 N/APP5 was not used because a reputable-source assertion alone is not sufficient evidence for classification here. Details ▾Hide ▴
BP6 N/ABP6 was not used because a reputable-source assertion alone is not sufficient evidence for classification here. Details ▾Hide ▴
BP7 N/ABP7 is a synonymous or noncoding splice-neutral criterion, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense consequence
- SpliceAI reviewed separately under computational evidence
Sources
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.906A>C
- Protein (HGVS p.)
- NP_009125.1:p.(Glu302Asp)
- GRCh38
- chr22:28703507 T>G
- GRCh37
- chr22:29099495 T>G
Gene diagram
Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.4. Select a row to find it on the plot.
CHEK2NM_007194.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in CHEK2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
14 / 1,437,854 alleles
AF 9.74e-06 · 1 homozygotes · FAF 6.1e-05
gnomAD v2.1
8 / 234,112 alleles
AF 3.42e-05 · 0 homozygotes · FAF 2.24e-05
By genetic ancestry
gnomAD v4.1
AF 9.7e-06 · 14 / 1,437,854 alleles · 1 hom · FAF 6.1e-05
| Middle Eastern2 / 5,762 | 0.000351 hom |
| Admixed American2 / 54,660 | 3.7e-05 |
| Remaining individuals1 / 56,382 | 1.8e-05 |
| European (non-Finnish)9 / 1,031,364 | 8.7e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.4e-05 · 8 / 234,112 alleles · 0 hom · FAF 2.2e-05
| Admixed American2 / 29,918 | 6.7e-05 |
| European (non-Finnish)6 / 101,258 | 5.9e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.73673e-06; MAF= 0.00097%, 14/1437854 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000347102; MAF= 0.03471%, 2/5762 alleles, homozygotes = 1); grpmax FAF= 6.098e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.41717e-05; MAF= 0.00342%, 8/234112 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.68494e-05; MAF= 0.00668%, 2/29918 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available computational evidence does not support a damaging prediction. SpliceAI shows no significant predicted splice effect with a maximum delta score of 0.01, REVEL is 0.41, and BayesDel is 0.0235302; taken together, these results do not reach a consistent damaging threshold for PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.41
- BayesDel 0.0235302
Still missing
- No CHEK2-specific computational calibration rule was available in the retrieved rule set.
Sources
BP4 Available computational evidence does not provide a consistent benign prediction. SpliceAI predicts no significant splice effect, but REVEL is 0.41 and BayesDel is 0.0235302, which together do not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.41
- BayesDel 0.0235302
Still missing
- No CHEK2-specific benign computational calibration rule was available in the retrieved rule set.
Sources
BP7 N/ABP7 is a synonymous or noncoding splice-neutral criterion, and this variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense consequence
- SpliceAI reviewed separately under computational evidence
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.41. BayesDel score = 0.0235302.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
14 / 1,437,854 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/128087/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29099495-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28703507-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.906A…
- OncoKB ↗www.oncokb.org/gene/CHEK2/E302D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.906A%3EC
- 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= 9.73673e-06; MAF= 0.00097%, 14/1437854 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000347102; MAF= 0.03471%, 2/5762 alleles, homozygotes = 1); grpmax FAF= 6.098e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.41717e-05; MAF= 0.00342%, 8/234112 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.68494e-05; MAF= 0.00668%, 2/29918 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.41. BayesDel score = 0.0235302.
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.