About CHEK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK1 c.709G>T, p.(Ala237Ser)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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
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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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_001274.5:c.709G>T is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present in only 1 of 1,595,844 alleles (AF=6.27e-7; 0.00006%) in gnomAD v4.1, with zero homozygotes. This is well below the 0.1% PM2 threshold for non-VCEP adjudication.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. CHEK1 germline disease is mediated by loss-of-function via truncating variants; a pathogenic germline splice variant (c.613+2T>C) causing kinase domain truncation has been reported in a family with multiple cancers (PMID:38686193). The variant under review, p.Ala237Ser, is a missense change in a gene where truncation is the established disease mechanism.
BP4Supporting
BP4 · supporting
BP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI delta score is 0.02 (no predicted splicing impact). Three independent computational predictors uniformly support a benign interpretation.
Recorded classification: Likely benign
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, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
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
1 / 1,595,844 alleles
gnomAD v4.1: 1 / 1,595,844 alleles. Recorded AF 6.26628e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
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: 3 met · 21 not met · 0 not assessed · 5 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.709G>T (p.Ala237Ser) in CHEK1 is a missense variant with extremely low population frequency (1/1,595,844 alleles in gnomAD v4.1; PM2 at supporting level).
Multiple computational predictors uniformly suggest a benign effect: REVEL 0.067, BayesDel -0.406, and SpliceAI max delta 0.02 (BP4 at supporting benign level).
CHEK1 germline disease is mediated by loss-of-function via truncating variants; a pathogenic splice variant (c.613+2T>C) causing kinase domain truncation has been reported in familial cancer (PMID:38686193). As a missense variant in a gene where truncation is the established disease mechanism, BP1 applies at supporting benign level.
By generic ACMG/AMP 2015 combination rules (PMID:25741868), two supporting benign criteria (BP1, BP4) with one supporting pathogenic criterion (PM2) yields a classification of Likely Benign.
No criteria match.
Met · 3
PM2 SupportingNM_001274.5:c.709G>T is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present in only 1 of 1,595,844 alleles (AF=6.27e-7; 0.00006%) in gnomAD v4.1, with zero homozygotes. This is well below the 0.1% PM2 threshold for non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 1/1
- 595
- 844 alleles (AF=6.27e-7)
- 0 homozygotes.
- gnomAD-Canada v1.0: absent.
Sources
BP1 SupportingBP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. CHEK1 germline disease is mediated by loss-of-function via truncating variants; a pathogenic germline splice variant (c.613+2T>C) causing kinase domain truncation has been reported in a family with multiple cancers (PMID:38686193). The variant under review, p.Ala237Ser, is a missense change in a gene where truncation is the established disease mechanism. Details ▾Hide ▴
Evidence considered
- CHEK1 germline disease mechanism is loss-of-function via truncating variants.
- Pathogenic CHEK1 c.613+2T>C splice variant (PMID:38686193) confirmed as truncating LoF allele causing familial cancer.
Sources
pvs1_gene_context
BP4 SupportingBP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI delta score is 0.02 (no predicted splicing impact). Three independent computational predictors uniformly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign prediction).
- BayesDel: -0.406 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact predicted).
Sources
Not met · 21 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change at the same position that results in the same amino acid change, with the other variant established as pathogenic. No such variant has been reported for codon 237 of CHEK1. Details ▾Hide ▴
Evidence considered
- No known pathogenic variant with the same amino acid change at this position.
PS2 PS2 requires a de novo observation with confirmed maternity and paternity. No de novo data are available for NM_001274.5:c.709G>T. Details ▾Hide ▴
Evidence considered
- No de novo observations reported in the literature or databases.
PS3 PS3 requires well-established functional studies demonstrating a damaging effect. No variant-specific functional data exist for NM_001274.5:c.709G>T. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. Computational predictors (REVEL 0.067, BayesDel -0.406) are benign, not supportive of a damaging effect. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence. REVEL 0.067 (benign)
- BayesDel -0.406 (benign).
Still missing
- No in vitro or in vivo functional studies available for this variant.
Sources
PS4 PS4 requires statistically significant enrichment of the variant in affected individuals compared to controls. The variant is absent from ClinVar and has not been reported in any case-control studies. The single allele in gnomAD v4.1 provides no disease-association signal. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar. No case-control or cohort enrichment data available.
Sources
PM1 PM1 requires location in a mutational hotspot or well-established critical functional domain without benign variation. Residue Ala237 is not a statistically significant hotspot per cancerhotspots.org. While Ala237 lies within the CHEK1 kinase domain, no domain-level PM1 framework has been established for CHEK1 in the absence of a VCEP, and sparse literature evidence alone is insufficient to apply generic PM1. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: not a significant hotspot. No domain-level PM1 framework available for CHEK1.
Still missing
- No CHEK1-specific domain-level PM1 framework or saturation mutagenesis data available.
PM5 PM5 requires a different pathogenic missense change at the same codon. The PM5 candidate search found no pathogenic missense variants at codon 237 (p.Ala237) of CHEK1 in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No pathogenic missense comparator identified at CHEK1 codon 237.
Sources
pm5_candidates
PM6 PM6 requires a de novo observation without confirmed maternity and paternity. No de novo observations of NM_001274.5:c.709G>T have been reported. Details ▾Hide ▴
Evidence considered
- No de novo observations available.
PP1 PP1 requires cosegregation with disease in multiple affected family members. No family segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. In CHEK1, the established germline disease mechanism is loss-of-function via truncating variants (e.g., c.613+2T>C splice variant causing kinase domain truncation; PMID:38686193), not missense alterations. No missense constraint data (Z-score) support low benign missense variation for CHEK1. Details ▾Hide ▴
Evidence considered
- CHEK1 disease mechanism is LoF/truncation
- not missense. No missense constraint metrics available.
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI max delta is 0.02 (no predicted splice impact). All available in silico predictors uniformly suggest a benign effect; none support a deleterious impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign).
- BayesDel: -0.406 (benign).
- SpliceAI max delta: 0.02 (no splicing impact).
Sources
PP4 PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology. No proband phenotype or family history data are available for this case. Details ▾Hide ▴
Evidence considered
- No phenotype or family history data provided.
PP5 PP5 requires a reputable source to have classified the variant as pathogenic. NM_001274.5:c.709G>T is absent from ClinVar. No expert panel or clinical laboratory has reported this variant. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source reports this variant as pathogenic.
Sources
BA1 BA1 requires an allele frequency >1% in population databases. The maximum observed frequency is 6.27e-7 (0.00006%) in gnomAD v4.1, far below the 1% threshold. Details ▾Hide ▴
BS1 BS1 requires an allele frequency >0.3% in population databases (non-VCEP cutoff). The maximum observed frequency is 6.27e-7 (0.00006%) in gnomAD v4.1, far below the 0.3% threshold. Details ▾Hide ▴
BS2 BS2 requires observation in a healthy adult individual for a fully penetrant disorder (in homozygous state, or in hemizygous/dominant state at frequency inconsistent with disease penetrance). Zero homozygotes are observed in gnomAD, and the single heterozygous carrier does not meet the threshold for BS2. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD. Single heterozygous carrier insufficient for BS2.
Sources
BS3 BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No functional studies have been performed on NM_001274.5:c.709G>T. In silico predictions alone do not satisfy BS3. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional studies available for this variant.
Still missing
- No functional studies exist for this variant.
BS4 BS4 requires lack of cosegregation with disease in affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
BP2 BP2 requires observation in trans with a pathogenic dominant variant or in cis with a pathogenic recessive variant. No phase data are available for NM_001274.5:c.709G>T. Details ▾Hide ▴
Evidence considered
- No phasing data available.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
BP6 BP6 requires a reputable source to have classified the variant as benign. NM_001274.5:c.709G>T is absent from ClinVar; no source reports it as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No reputable source reports this variant as benign.
Sources
PS5 PS5 requires a different pathogenic variant at the same amino acid position classified by a reputable source. PM5 candidate search identified no pathogenic missense comparators at codon 237 (p.Ala237) of CHEK1. Details ▾Hide ▴
Evidence considered
- No pathogenic variant identified at the same residue in ClinVar or the literature.
Sources
pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001274.5:c.709G>T is a missense variant (p.Ala237Ser) and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). PVS1 is not applicable to missense variants under generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not eligible for PVS1 under PMC6185798 null-variant framework.
Sources
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans. CHEK1-associated cancer predisposition is not established as a recessive condition, and no trans data are available. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to non-repeat in-frame insertions/deletions and stop-loss variants causing protein length change. This is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001274.5:c.709G>T is a missense variant (p.Ala237Ser), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CHEK1
- Transcript
- NM_001274.5
- Coding (HGVS c.)
- NM_001274.5:c.709G>T
- Protein (HGVS p.)
- NP_001265.2:p.(Ala237Ser)
- GRCh38
- chr11:125635524 G>T
- GRCh37
- chr11:125505419 G>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
1 / 1,595,844 alleles
AF 6.27e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.3e-07 · 1 / 1,595,844 alleles · 0 hom
| European (non-Finnish)1 / 1,169,916 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.26628e-07; MAF= 0.00006%, 1/1595844 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54762e-07; MAF= 0.00009%, 1/1169916 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.067
- BayesDel
- -0.406
How the predictions were used
BP4 SupportingBP4 requires multiple lines of computational evidence suggesting no impact on gene product. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI delta score is 0.02 (no predicted splicing impact). Three independent computational predictors uniformly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign prediction).
- BayesDel: -0.406 (benign prediction).
- SpliceAI max delta: 0.02 (no splice impact predicted).
Sources
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.067 (strongly predictive of benign), BayesDel score is -0.406 (predictive of benign), and SpliceAI max delta is 0.02 (no predicted splice impact). All available in silico predictors uniformly suggest a benign effect; none support a deleterious impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign).
- BayesDel: -0.406 (benign).
- SpliceAI max delta: 0.02 (no splicing impact).
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001274.5:c.709G>T is a missense variant (p.Ala237Ser), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.067. BayesDel score = -0.405592.
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
1 / 1,595,844 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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.709G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-125505419-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-125635524-G-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-125635524-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001274.5%3Ac.709G…
- OncoKB ↗www.oncokb.org/gene/CHEK1/A237S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK1+c.709G%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
This variant is present in gnomAD v4.1 (AF= 6.26628e-07; MAF= 0.00006%, 1/1595844 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.54762e-07; MAF= 0.00009%, 1/1169916 alleles, homozygotes = 0).
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 = 0.02). REVEL score = 0.067. BayesDel score = -0.405592.
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.