About CHEK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK1 c.1148A>T, p.(Lys383Ile)
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.1148A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% population frequency for non-VCEP generic ACMG assessment.
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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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.
29 criteria with recorded statuses: 1 met · 19 not met · 3 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
NM_001274.5:c.1148A>T (p.Lys383Ile) is a missense variant in CHEK1. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
No pathogenic or likely pathogenic classifications exist in ClinVar. No functional studies, de novo reports, co-segregation data, or case-control evidence are available for this variant.
In silico predictors are discordant: REVEL 0.433 is intermediate, BayesDel -0.14524 is benign-leaning, and SpliceAI predicts no splicing impact (max delta 0.01). The computational evidence does not meet PP3 or BP4 thresholds.
CHEK1 lacks ClinGen-curated gene-disease validity, and no CSPEC or VCEP framework is available. Criteria dependent on established disease association (PP2, PP4) could not be reliably assessed.
Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868), the single supporting pathogenic criterion (PM2) is insufficient to reach Likely Pathogenic, and no benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingNM_001274.5:c.1148A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% population frequency for non-VCEP generic ACMG assessment. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD population databases (v2.1
- v4.1
- Canada).
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No pathogenic variant at the same amino acid position (Lys383) arising from a different nucleotide change has been reported in ClinVar or the literature. No comparator variants were identified. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-residue pathogenic comparators identified.
Still missing
- No systematic search for literature-only pathogenic variants at position 383.
Sources
PS2 No de novo occurrence of NM_001274.5:c.1148A>T has been reported in any database or publication, with or without confirmed parentage. Details ▾Hide ▴
Evidence considered
- Exploratory search found no de novo reports in ClinVar
- denovo-db
- or the literature.
Still missing
- No targeted de novo testing has been performed for this variant.
Sources
PS3 No functional study has evaluated the biological effect of p.Lys383Ile in a validated assay measuring CHEK1 kinase activity, DNA damage response, or cell cycle checkpoint function. Details ▾Hide ▴
Evidence considered
- OncoKB reports unknown oncogenic effect
- no variant-specific functional data in curated databases or literature.
Still missing
- No experimental functional characterization of p.K383I has been performed.
Sources
PS4 No case-control study or cohort analysis demonstrates enrichment of this variant in affected individuals compared to controls. The variant is absent from ClinVar and gnomAD, precluding any prevalence comparison. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1
- v4.1
- and ClinVar
- no case-control data available.
Still missing
- No cohort studies have specifically screened CHEK1 c.1148A>T in affected populations.
Sources
PM1 The variant lies in the C-terminal regulatory domain (residues ~266-476), outside the protein kinase domain (residues 10-265). No mutational hotspot or critical functional domain enriched for pathogenic missense variants has been defined in this region of CHEK1. Details ▾Hide ▴
Evidence considered
- Variant located at residue 383 in the C-terminal regulatory domain
- not within a defined critical domain or mutational hotspot.
Still missing
- CHEK1 domain-level constraint data not available from HCI prior or similar resources.
PM6 No de novo event with confirmed maternity and paternity has been reported for this variant in any database or publication. Details ▾Hide ▴
Evidence considered
- Exploratory search found no de novo reports for this variant.
Still missing
- No family studies with parent-of-origin testing have been conducted.
PP1 No co-segregation data are available for this variant. No multigenerational family studies demonstrating co-segregation of c.1148A>T with a CHEK1-associated phenotype have been reported. Details ▾Hide ▴
Evidence considered
- Exploratory search found no family co-segregation data.
Still missing
- No family studies have been performed for carriers of this variant.
PP3 In silico predictors do not provide multiple consistent lines of evidence supporting a deleterious effect. REVEL score is 0.433 (below typical pathogenic threshold of 0.5), BayesDel is -0.14524 (benign-leaning), and SpliceAI max delta is 0.01 (no predicted splicing impact). The computational evidence is discordant and does not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.433 (intermediate)
- BayesDel -0.14524 (benign-leaning)
- SpliceAI max delta 0.01 (no effect).
Still missing
- No gene-specific in silico calibration for CHEK1 is available.
Sources
PP5 No reputable clinical diagnostic laboratory or expert panel has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no clinical laboratory classifications available.
Sources
BA1 BA1 requires allele frequency >1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD datasets
- BA1 threshold (>1%) not met.
Sources
BS1 BS1 requires allele frequency >0.3% in population databases for non-VCEP assessment. This variant is absent from all gnomAD datasets. Details ▾Hide ▴
Evidence considered
- Variant absent from all gnomAD datasets
- BS1 threshold (>0.3%) not met.
Sources
BS2 BS2 requires observation in a healthy adult individual in the homozygous state or in trans with a known pathogenic variant, for a gene associated with a fully penetrant dominant disorder. This variant is absent from population databases and no such observation exists. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no homozygous or in-trans observations available.
Sources
BS3 No functional study has demonstrated that p.Lys383Ile does not alter CHEK1 protein function in a validated assay. BS3 requires positive evidence of no functional impact. Details ▾Hide ▴
Evidence considered
- Exploratory search found no functional studies evaluating this variant for normal function.
Still missing
- No experimental data exist to demonstrate absence of functional effect.
BS4 No family studies demonstrating lack of segregation with disease are available for this variant. Details ▾Hide ▴
Evidence considered
- No non-segregation data available.
Still missing
- No family-based segregation analysis has been performed.
BP1 BP1 requires that a missense variant occurs in a gene where only truncating variants are known to cause disease. CHEK1 lacks established gene-disease validity; there is no evidence demonstrating that truncating variants are the exclusive disease mechanism. Details ▾Hide ▴
Evidence considered
- Insufficient evidence that only truncating CHEK1 variants cause disease
- gene-disease validity not established.
Still missing
- CHEK1 gene-disease relationship not curated by ClinGen.
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder. No such observation exists for this variant, and CHEK1 is not established as a dominant disease gene. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic CHEK1 variant.
BP4 In silico predictors show discordant results. REVEL score is 0.433 (intermediate, not clearly benign), BayesDel is -0.14524 (benign-leaning), and SpliceAI max delta is 0.01 (no splicing impact). The evidence is not consistently supportive of no impact; REVEL does not confidently predict benign. Details ▾Hide ▴
Evidence considered
- REVEL 0.433 (intermediate)
- BayesDel -0.14524 (benign-leaning)
- SpliceAI 0.01 (no effect). Discordant results do not meet BP4 threshold for 'multiple lines suggesting no impact.'
Sources
BP6 BP6 requires a reputable source to classify the variant as benign. This variant is absent from ClinVar; no clinical laboratory or expert panel has classified it as benign. Details ▾Hide ▴
PS5 No pathogenic missense variant at position Lys383 has been established. PS5 requires a different pathogenic missense at the same residue, which has not been reported. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variants at CHEK1 residue 383 identified in ClinVar.
Sources
Not assessed · 3 · no assessment recorded
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. CHEK1 lacks established ClinGen gene-disease validity, and HCI prior scores are unavailable for this gene. Without these prerequisites, PP2 cannot be reliably applied. Details ▾Hide ▴
Evidence considered
- No gene-disease validity established for CHEK1
- HCI prior score not available.
Still missing
- CHEK1 lacks ClinGen gene-disease validity curation
- missense constraint metrics not available.
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No case-level phenotype or family history information is available for adjudication, and CHEK1 lacks a well-defined Mendelian disease association. Details ▾Hide ▴
Evidence considered
- No phenotype or family history data provided for this case.
Still missing
- Case-level phenotype data not available
- CHEK1 disease spectrum not well defined.
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No case-level phenotype data or alternate molecular diagnosis information is available for assessment. Details ▾Hide ▴
Evidence considered
- No case-level clinical data provided.
Still missing
- Case phenotype and any alternate molecular diagnoses unknown.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Lys383Ile) and does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus variants). The generic PVS1 framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a null variant
- generic PVS1 framework does not apply.
Sources
PM3 N/APM3 applies to recessive disorders. CHEK1 is not associated with a recessive disease, and no reports of biallelic CHEK1 variants exist. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a single nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variants at the same residue (Lys383) have been identified. The automated PM5 candidate search found zero comparator variants at this position. PM5 requires an established pathogenic variant at the same amino acid residue with a different amino acid change. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparator variants.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (p.Lys383Ile), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CHEK1
- Transcript
- NM_001274.5
- Coding (HGVS c.)
- NM_001274.5:c.1148A>T
- Protein (HGVS p.)
- NP_001265.2:p.(Lys383Ile)
- GRCh38
- chr11:125644558 A>T
- GRCh37
- chr11:125514453 A>T
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
- 0.433
- BayesDel
- -0.145
How the predictions were used
PP3 In silico predictors do not provide multiple consistent lines of evidence supporting a deleterious effect. REVEL score is 0.433 (below typical pathogenic threshold of 0.5), BayesDel is -0.14524 (benign-leaning), and SpliceAI max delta is 0.01 (no predicted splicing impact). The computational evidence is discordant and does not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.433 (intermediate)
- BayesDel -0.14524 (benign-leaning)
- SpliceAI max delta 0.01 (no effect).
Still missing
- No gene-specific in silico calibration for CHEK1 is available.
Sources
BP4 In silico predictors show discordant results. REVEL score is 0.433 (intermediate, not clearly benign), BayesDel is -0.14524 (benign-leaning), and SpliceAI max delta is 0.01 (no splicing impact). The evidence is not consistently supportive of no impact; REVEL does not confidently predict benign. Details ▾Hide ▴
Evidence considered
- REVEL 0.433 (intermediate)
- BayesDel -0.14524 (benign-leaning)
- SpliceAI 0.01 (no effect). Discordant results do not meet BP4 threshold for 'multiple lines suggesting no impact.'
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (p.Lys383Ile), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.433. BayesDel score = -0.14524.
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 0.010
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001274.5%3Ac.1148A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-125514453-A-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-125644558-A-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-125644558-A-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001274.5%3Ac.1148…
- OncoKB ↗www.oncokb.org/gene/CHEK1/K383I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK1+c.1148A%3ET
- 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.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.433. BayesDel score = -0.14524.
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.