About CHEK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK1 c.157A>G, p.(Lys53Glu)
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 Not recorded. 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
NM_001274.5:c.157A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all populations (<0.1% threshold).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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 ↗
No screenshot for this evidence
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. CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies.
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 Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 4 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001274.5:c.157A>G (p.Lys53Glu) in CHEK1 is a missense variant absent from all gnomAD population databases (v2.1, v4.1, Canada), meeting PM2 at supporting strength.
No pathogenic or likely pathogenic variant has been reported at the same amino acid residue (Lys53) in ClinVar; PS1 and PM5 are not applicable.
Multiple lines of in silico evidence do not support a deleterious effect: REVEL 0.271, BayesDel -0.154, SpliceAI max delta 0.00. PP3 is not met.
PVS1 is not applicable as this is a missense variant not falling into null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798).
No functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control data (PS4), phenotype data (PP4), or ClinVar classifications (PS5/PP5/BP6) are available for this variant.
With PM2_supporting as the sole met criterion, the variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 rules.
No criteria match.
Met · 1
PM2 SupportingNM_001274.5:c.157A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all populations (<0.1% threshold). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF=0). Absent from gnomAD v4.1 (AF=0). Absent from gnomAD-Canada v1.0 (AF=0.0).
Sources
Not met · 4 · evaluated, threshold not reached
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.271 (<0.5 threshold), BayesDel score -0.154 (<0.27 threshold), and SpliceAI max delta 0.00 (no splice impact) all indicate a neutral or benign in silico profile. Details ▾Hide ▴
Evidence considered
- REVEL: 0.271 (benign). BayesDel: -0.154 (intermediate/benign). SpliceAI: max delta 0.00 (no splice impact).
Sources
BA1 Variant is absent from all gnomAD populations (AF=0). Does not meet the BA1 threshold of >1% allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0. gnomAD v4.1: AF=0. Both far below 1% BA1 threshold.
Sources
BS1 Variant is absent from all gnomAD populations (AF=0). Does not meet the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0. gnomAD v4.1: AF=0. Both far below 0.3% BS1 threshold.
Sources
BP4 Computational evidence is mixed and does not meet the 'multiple lines suggesting no impact' threshold. REVEL 0.271 and SpliceAI 0.00 suggest no impact, but BayesDel -0.154 is intermediate and does not provide a clear benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.271 (benign-leaning). BayesDel: -0.154 (intermediate
- not clearly benign). SpliceAI: 0.00 (no impact). Mixed signal.
Sources
Not assessed · 13 · no assessment recorded
PS3 No well-established functional studies evaluate the specific variant NM_001274.5:c.157A>G. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No COSMIC data. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific evidence. COSMIC: not found.
Still missing
- No functional assay data for this specific missense change.
Sources
PS4 No case-control or cohort studies include this variant. Absent from ClinVar and COSMIC. The variant has not been reported in affected individuals relative to controls. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- COSMIC
- and all literature sources.
Still missing
- No case-control or cohort data available.
PM1 Position 53 lies within the CHEK1 kinase domain (residues ~1-265), but no VCEP/CSPEC defines this residue as a mutational hotspot or critical functional domain position. Cancer Hotspots analysis found no statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
- Residue K53 within kinase domain
- but not in a statistically significant hotspot per Cancer Hotspots. No CSPEC-defined critical domain.
Still missing
- No VCEP-defined mutational hotspots or critical domain residues for CHEK1.
PP1 No segregation data available. No family studies or co-segregation analyses include this variant. Details ▾Hide ▴
Evidence considered
- No segregation data in any available source.
Still missing
- No segregation or family study data.
PP2 HCI prior data not available for CHEK1. Cannot determine whether the gene has a low rate of benign missense variation. Without HCI prior or CSPEC specification, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not found for CHEK1 (gene not supported).
Still missing
- HCI prior probability not available for CHEK1.
PP4 No phenotype data available. The variant has not been identified in patients with CHEK1-related disease phenotypes in ClinVar or published literature. Details ▾Hide ▴
Evidence considered
- No phenotype information in available sources.
Still missing
- No patient phenotype data available.
PP5 No reputable source has classified this variant as pathogenic. No ClinVar submissions exist, and no expert panel has evaluated this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: no submissions
- no classification
- no expert panel review.
Still missing
- No expert panel or reputable source classification available.
Sources
BS2 No observations in healthy adult controls or homozygous state available. No individual-level data to evaluate BS2. Details ▾Hide ▴
Evidence considered
- No individual-level observation data available.
Still missing
- No healthy control observation data.
BS3 No well-established functional studies have evaluated the specific effect of p.Lys53Glu on CHEK1 protein function. In silico predictors suggest neutral effect but do not constitute BS3-level functional evidence. Details ▾Hide ▴
Evidence considered
- No functional assay data available for this variant. OncoKB reports no variant-specific evidence.
Still missing
- No functional studies for this specific variant.
BS4 No segregation data available to assess lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation or family data available.
Still missing
- No segregation data.
BP1 Although CHEK1 loss-of-function is a supported disease mechanism with truncating variants implicated (PMID:38686193), insufficient evidence exists to determine that primarily truncating variants cause CHEK1-related disease such that a missense change should be downgraded. No CSPEC/VCEP specification available. Details ▾Hide ▴
Evidence considered
- CHEK1 LOF mechanism supported
- but no CSPEC specification that primarily truncating variants cause disease.
Still missing
- No VCEP determination of variant spectrum for CHEK1.
BP2 No phase information available. No observations in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- No phase or co-occurrence data available.
Still missing
- No phase information.
PS5 No ClinVar submissions exist for this variant. No alternative-source pathogenic classification is available for evaluation. Details ▾Hide ▴
Evidence considered
- ClinVar: zero submissions
- zero variation IDs.
Still missing
- No ClinVar classification available.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001274.5:c.157A>G is a missense variant (p.Lys53Glu) and does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice) required for generic PVS1 application under PMC6185798. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false per PVS1 variant assessment.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo pathogenic variant with a different amino acid substitution at the same residue (Lys53) has been identified. PM5 candidate search returned zero same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator variants found at Lys53.
Sources
pm5_candidates
PS2 N/ANo de novo observation data available. No ClinVar submissions, no literature reports, and no family studies documenting de novo occurrence of this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PM5 N/ANo same-residue comparator variants with alternative pathogenic substitutions identified at Lys53. PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: zero same-residue candidates
- zero expert-panel pathogenic comparators.
Sources
pm5_candidates
PM6 N/ANo de novo observation reported. No family data or trio testing results available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar or literature.
Still missing
- No trio or parent-of-origin testing data.
BP5 N/ANo observations of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has reported this variant as benign. No ClinVar submissions or literature classifications exist. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants. NM_001274.5:c.157A>G is a missense variant (p.Lys53Glu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- CHEK1
- Transcript
- NM_001274.5
- Coding (HGVS c.)
- NM_001274.5:c.157A>G
- Protein (HGVS p.)
- NP_001265.2:p.(Lys53Glu)
- GRCh38
- chr11:125627698 A>G
- GRCh37
- chr11:125497593 A>G
Gene diagram
Every interpreted variant in CHEK1, mapped onto the exon structure of NM_001274.5. Select a row to find it on the plot.
CHEK1NM_001274.5
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 CHEK1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.271
- BayesDel
- -0.154
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.271 (<0.5 threshold), BayesDel score -0.154 (<0.27 threshold), and SpliceAI max delta 0.00 (no splice impact) all indicate a neutral or benign in silico profile. Details ▾Hide ▴
Evidence considered
- REVEL: 0.271 (benign). BayesDel: -0.154 (intermediate/benign). SpliceAI: max delta 0.00 (no splice impact).
Sources
BP4 Computational evidence is mixed and does not meet the 'multiple lines suggesting no impact' threshold. REVEL 0.271 and SpliceAI 0.00 suggest no impact, but BayesDel -0.154 is intermediate and does not provide a clear benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.271 (benign-leaning). BayesDel: -0.154 (intermediate
- not clearly benign). SpliceAI: 0.00 (no impact). Mixed signal.
Sources
BP7 N/ABP7 applies to synonymous variants. NM_001274.5:c.157A>G is a missense variant (p.Lys53Glu), not synonymous. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.271. BayesDel score = -0.154117.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001274.5%3Ac.157A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-125497593-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-125627698-A-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-125627698-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001274.5%3Ac.157A…
- OncoKB ↗www.oncokb.org/gene/CHEK1/K53E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK1+c.157A%3EG
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.271. BayesDel score = -0.154117.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies.
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.