About CHEK1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK1 c.965G>A, p.(Arg322His)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in gnomAD population databases: v2.1 overall AF=0.004% (10/251,222 alleles, 0 homozygotes) and v4.1 overall AF=0.002% (36/1,613,908 alleles, 0 homozygotes), both well below the 0.1% PM2 threshold. Maximum subpopulation frequency is 0.0275% (South Asian, v4.1). Downgraded to supporting strength given the variant is not completely absent and the limited germline disease association of CHEK1.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no damaging effect: REVEL score 0.055 (well below the 0.29 benign threshold), BayesDel score -0.267 (negative, indicating benign), and SpliceAI max delta 0.03 (no predicted splice impact). Three independent in silico tools unanimously predict a neutral/benign effect.
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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
36 / 1,613,908 alleles
gnomAD v4.1: 36 / 1,613,908 alleles. Recorded AF 2.23061e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98054e-05; MAF= 0.00398%, 10/251222 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196477; MAF= 0.01965%, 6/30538 alleles, homozygotes = 0); grpmax FAF= 8.528e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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: 2 met · 21 not met · 0 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
This variant (NM_001274.5:c.965G>A, p.Arg322His) is a missense substitution in CHEK1, a gene with limited but emerging evidence for germline loss-of-function disease association. No CSPEC or VCEP framework exists for CHEK1; assessment follows generic ACMG/AMP 2015 guidelines.
The variant is observed at extremely low frequency in gnomAD population databases (v2.1 AF=0.004%, v4.1 AF=0.002%), meeting the PM2 criterion at supporting strength.
Multiple in silico predictors unanimously suggest a neutral effect: REVEL score 0.055, BayesDel score -0.267, and SpliceAI max delta 0.03, meeting BP4 at supporting_benign strength.
ClinVar reports this variant as Uncertain significance (VCV2397701, criteria provided, single submitter: Ambry Genetics). There are no reputable sources classifying this variant as pathogenic or benign.
No variant-specific functional studies, de novo observations, segregation data, or case-control enrichment data were identified in the available literature or databases.
The final evidence profile includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). These cancel, resulting in a classification of Uncertain significance per the ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in gnomAD population databases: v2.1 overall AF=0.004% (10/251,222 alleles, 0 homozygotes) and v4.1 overall AF=0.002% (36/1,613,908 alleles, 0 homozygotes), both well below the 0.1% PM2 threshold. Maximum subpopulation frequency is 0.0275% (South Asian, v4.1). Downgraded to supporting strength given the variant is not completely absent and the limited germline disease association of CHEK1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.98e-05 (10/251
- 222 alleles)
- grpmax FAF=8.53e-05
- gnomAD v4.1: AF=2.23e-05 (36/1
- 613
- 908 alleles)
- grpmax FAF=0.00019
- Max subpop AF: SAS 0.0275% (v4.1)
Sources
BP4 SupportingMultiple lines of computational evidence predict no damaging effect: REVEL score 0.055 (well below the 0.29 benign threshold), BayesDel score -0.267 (negative, indicating benign), and SpliceAI max delta 0.03 (no predicted splice impact). Three independent in silico tools unanimously predict a neutral/benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign range
- below 0.29 threshold)
- BayesDel: -0.267 (negative score
- benign-leaning)
- SpliceAI: max delta 0.03 (no predicted splice alteration)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No evidence identified of a different nucleotide change at codon 322 producing the same p.Arg322His substitution that has been classified as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2397701 lists only this single nucleotide variant
- no alternate nucleotide change at this codon producing p.Arg322His is reported as pathogenic.
Still missing
- No alternate nucleotide change causing p.Arg322His identified in ClinVar or literature.
Sources
PS2 No de novo occurrence data available for this variant. PS2 requires confirmation of de novo origin with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar submissions or literature.
Still missing
- No parental testing data available.
PS3 No variant-specific or systematically characterized range functional data identified for CHEK1 p.Arg322His. OncoKB reports unknown oncogenic effect with no curated functional studies. The REVEL score of 0.055 and BayesDel score of -0.266 are computational predictions, not experimental functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies.
- No experimental functional data found in literature.
Still missing
- No experimental functional studies (in vitro or in vivo) identified for this variant.
Sources
PS4 No case-control data or statistically significant enrichment data available comparing prevalence of this variant in affected individuals versus general population controls. Details ▾Hide ▴
Evidence considered
- No case-control or enrichment data available.
Still missing
- No affected-individual prevalence data available.
PM1 Position p.Arg322 lies in the SQ/TQ cluster domain (SCD) of CHEK1, a regulatory region involved in checkpoint signaling. However, this specific residue is not a statistically significant hotspot (cancerhotspots.org negative), and no well-established critical functional domain annotation supports PM1 at this exact residue within the broader SCD region. Domain-level inference from the literature is insufficient without direct evidence that position 322 is functionally critical. Details ▾Hide ▴
Evidence considered
- Hotspots: residue not significant.
- OncoKB: no functional annotation for this specific residue.
Still missing
- No domain-specific functional data establishing position 322 as critical.
Sources
PM6 No de novo occurrence data available for this variant. PM6 requires a de novo observation without confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo observations reported.
Still missing
- No de novo data available.
PP1 No co-segregation data with disease in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family studies available.
PP2 CHEK1 has not been established as a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Insufficient constraint data to support PP2. Details ▾Hide ▴
Evidence considered
- No gnomAD missense constraint data or gene-level evidence of low benign missense tolerance available.
Still missing
- No missense constraint metrics available for CHEK1.
PP3 Multiple lines of computational evidence predict a benign effect: REVEL score 0.055 (well below pathogenic threshold), BayesDel score -0.267 (negative, benign-leaning), and SpliceAI max delta 0.03 (no predicted splice impact). These scores do not support a deleterious effect and therefore do not meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign-leaning)
- BayesDel: -0.267 (benign-leaning)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
PP4 No patient phenotype or family history data are available to assess whether the phenotype is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype data available.
Still missing
- No clinical phenotype information provided.
PP5 ClinVar classification for this variant is Uncertain significance (1-star, single submitter: Ambry Genetics), not Pathogenic. PP5 requires a reputable source reporting the variant as pathogenic; a VUS classification does not satisfy this criterion even at supporting strength. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2397701: Uncertain significance
- criteria provided
- single submitter.
Sources
BA1 Maximum population allele frequency in gnomAD is 0.0275% (South Asian, v4.1), well below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpop AF: 0.0275% (SAS)
- well below 1% BA1 threshold
- gnomAD v2.1 max subpop AF: 0.0197% (SAS)
Sources
BS1 Maximum population allele frequency in gnomAD is 0.0275% (South Asian, v4.1), well below the 0.3% BS1 threshold. This variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpop AF: 0.0275% (SAS)
- well below 0.3% BS1 threshold
- gnomAD v2.1 max subpop AF: 0.0197% (SAS)
Sources
BS2 No evidence that this variant has been observed in a healthy adult individual for a fully penetrant disorder with a recessive or dominant inheritance pattern relevant to CHEK1. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No phenotype data for gnomAD allele carriers.
BS3 No well-established in vitro or in vivo functional studies demonstrate a neutral effect for CHEK1 p.Arg322His. Computational predictions (REVEL 0.055, BayesDel -0.267) are in silico tools, not experimental functional evidence meeting BS3 requirements. Details ▾Hide ▴
Evidence considered
- No experimental functional studies showing no deleterious effect identified.
- REVEL 0.055 and BayesDel -0.267 are computational
- not functional data.
Still missing
- No experimental functional studies available.
Sources
revelbayesdel
BS4 No segregation data available to assess lack of co-segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family studies available.
BP1 Although loss-of-function is supported as a disease mechanism for CHEK1 (based on germline literature review), CHEK1 has not been established as a gene where ONLY truncating variants cause disease. Missense variants are also plausible in the kinase and regulatory domains, and BP1 is not met. Details ▾Hide ▴
Evidence considered
- CHEK1 LOF mechanism supported but gene not established as exclusively truncating-variant disease gene.
Sources
pvs1_gene_context
BP2 No data available on whether this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No trans/cis phase data available.
Still missing
- No phase data available.
BP5 No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No clinical case data with alternate molecular diagnosis.
BP6 ClinVar classification for this variant is Uncertain significance (1-star, single submitter), not Benign or Likely Benign. BP6 requires a reputable source reporting the variant as benign; a VUS classification does not satisfy this criterion. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2397701: Uncertain significance
- criteria provided
- single submitter.
Sources
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter; Ambry Genetics). PS5 requires a reputable source recently reporting the variant as pathogenic where independent evaluation is not possible. Details ▾Hide ▴
Evidence considered
- ClinVar VCV2397701: Uncertain significance
- 1 clinical laboratory.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.965G>A, p.Arg322His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- does not fall into PVS1 null-variant buckets.
Sources
PM3 N/ANo evidence of biallelic inheritance pattern (trans with a pathogenic variant) relevant to CHEK1. PM3 applies to recessive disorders; CHEK1-associated cancer predisposition is primarily assessed under autosomal dominant models. Details ▾Hide ▴
Evidence considered
- No biallelic inheritance data
- CHEK1 disease model is not recessive.
PM4 N/AThis is a substitution variant, not an in-frame deletion/insertion or stop-loss variant. PM4 applies only to protein length changes due to in-frame indels or stop-loss variants in non-repeat regions. Details ▾Hide ▴
Evidence considered
- Substitution variant
- PM4 is for protein length-altering variants only.
PM5 N/ANo same-residue (p.Arg322) pathogenic missense comparator variants were identified in ClinVar; automated PM5 candidate harvesting could not confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidates: 0 same-residue candidates identified.
Sources
pm5_candidates
BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion. BP3 applies only to in-frame deletions/insertions in a repetitive region without a known function. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 is for in-frame indels only.
BP7 N/AThis is a missense variant (c.965G>A, p.Arg322His), not a synonymous variant. BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Identifiers
- Gene
- CHEK1
- Transcript
- NM_001274.5
- Coding (HGVS c.)
- NM_001274.5:c.965G>A
- Protein (HGVS p.)
- NP_001265.2:p.(Arg322His)
- GRCh38
- chr11:125644132 G>A
- GRCh37
- chr11:125514027 G>A
- ClinVar
- 2397701
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
36 / 1,613,908 alleles
AF 2.23e-05 · 0 homozygotes · FAF 0.00019
gnomAD v2.1
10 / 251,222 alleles
AF 3.98e-05 · 0 homozygotes · FAF 8.53e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.2e-05 · 36 / 1,613,908 alleles · 0 hom · FAF 0.00019
| South Asian25 / 91,008 | 0.00027 |
| African/African American2 / 74,994 | 2.7e-05 |
| Admixed American1 / 59,958 | 1.7e-05 |
| European (non-Finnish)8 / 1,179,988 | 6.8e-06 |
0 alternate alleles recorded in 6 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 4e-05 · 10 / 251,222 alleles · 0 hom · FAF 8.5e-05
| South Asian6 / 30,538 | 0.0002 |
| East Asian1 / 18,378 | 5.4e-05 |
| Admixed American1 / 34,512 | 2.9e-05 |
| European (non-Finnish)2 / 113,680 | 1.8e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.23061e-05; MAF= 0.00223%, 36/1613908 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000274701; MAF= 0.02747%, 25/91008 alleles, homozygotes = 0); grpmax FAF= 0.00019002.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98054e-05; MAF= 0.00398%, 10/251222 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196477; MAF= 0.01965%, 6/30538 alleles, homozygotes = 0); grpmax FAF= 8.528e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.055
- BayesDel
- -0.267
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no damaging effect: REVEL score 0.055 (well below the 0.29 benign threshold), BayesDel score -0.267 (negative, indicating benign), and SpliceAI max delta 0.03 (no predicted splice impact). Three independent in silico tools unanimously predict a neutral/benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign range
- below 0.29 threshold)
- BayesDel: -0.267 (negative score
- benign-leaning)
- SpliceAI: max delta 0.03 (no predicted splice alteration)
Sources
PP3 Multiple lines of computational evidence predict a benign effect: REVEL score 0.055 (well below pathogenic threshold), BayesDel score -0.267 (negative, benign-leaning), and SpliceAI max delta 0.03 (no predicted splice impact). These scores do not support a deleterious effect and therefore do not meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign-leaning)
- BayesDel: -0.267 (benign-leaning)
- SpliceAI: max delta 0.03 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.965G>A, p.Arg322His), not a synonymous variant. BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.055. BayesDel score = -0.266804.
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
36 / 1,613,908 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2397701/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-125514027-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-125644132-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-125644132-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001274.5%3Ac.965G…
- OncoKB ↗www.oncokb.org/gene/CHEK1/R322H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK1+c.965G%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= 2.23061e-05; MAF= 0.00223%, 36/1613908 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000274701; MAF= 0.02747%, 25/91008 alleles, homozygotes = 0); grpmax FAF= 0.00019002.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98054e-05; MAF= 0.00398%, 10/251222 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000196477; MAF= 0.01965%, 6/30538 alleles, homozygotes = 0); grpmax FAF= 8.528e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2397701)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.055. BayesDel score = -0.266804.
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.