CHEK1 encodes checkpoint kinase 1, a serine/threonine kinase that is central to the DNA damage response: it pauses cell cycle progression when DNA is damaged or unreplicated, giving cells time to repair the damage or trigger cell death. It acts downstream of the ATR and ATM kinases and helps maintain genome stability, notably by preventing cells from entering mitosis with damaged chromosomes. CHEK1 mutations are extremely rare in human disease, but the protein is frequently overproduced in several cancer types, including breast, non-small cell lung, and nasopharyngeal cancers, where it helps tumor cells survive DNA damage.
This variant
CHEK1 encodes checkpoint kinase 1, a DNA-damage-response kinase, and germline mutations in CHEK1 are extremely rare in human disease. This missense variant, p.(Arg162Cys), is rare in population databases, but with no functional, segregation, or case-control evidence, its effect on the kinase's DNA-damage-response function cannot be determined. The Uncertain Significance classification reflects that neither pathogenic nor benign evidence currently exists for this variant.
Transcript
NM_001274.5
HGVS · transcript:coding
NM_001274.5:c.484C>T
GRCh38
chr11:125633222 C>T
GRCh37
chr11:125503117 C>T
BasisNo CHEK1-specific classification framework is available, so the generic ACMG/AMP 2015 rules apply; with only PM2 met (supporting strength), no combination rule is satisfied and the variant is classified as Uncertain Significance.▾
No CHEK1-specific classification framework is available, so the generic ACMG/AMP 2015 rules apply; with only PM2 met (supporting strength), no combination rule is satisfied and the variant is classified as Uncertain Significance.
Classification rationale
PM2VUS
CHEK1 c.484C>Tmissense · exon 6
PM2 (Supporting): gnomAD v4.1 overall allele frequency is 0.00125%, below the 0.1% rarity threshold, with no homozygotes. Final: only PM2 is met at supporting strength, no ACMG/AMP 2015 combination rule is satisfied, and the variant is classified as Uncertain Significance (VUS).
PM2→VUS
Gene diagram
· NM_001274.5 · variants mapped to exon structure
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—click a row to locate it on the plot · use the link column to open its page
Variant ↕
Protein
Location
Classification
Link
Applied criteria · 1 applied · 23 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
PM2supportingPathogenic
Met (supporting): gnomAD v4.1 overall allele frequency is 0.00125%, far below the 0.1% PM2 rarity threshold, with no homozygotes.
gnomAD v4.1 reports 20/1,604,350 alleles (AF 0.00125%), East Asian AF 0.00450% (2/44,492), joint grpmax FAF 0.00088%, and zero homozygotes.gnomAD v2.1 independently reports 3/241,802 alleles (AF 0.00124%), highest observed Admixed American AF 0.00320% (1/31,218), grpmax FAF 0.000298%, and zero homozygotes.The gnomAD-Canada query was recorded as unavailable with HTTP 500 rather than as a confirmed absence.
Assessed · not applied
· 7 not met · 16 not assessed
Pathogenic
PS1Not met: no ClinVar record exists for this position, and no established pathogenic variant producing p.(Arg162Cys) from a different nucleotide change was found.
PS2Not assessed: no parental testing or parentage-confirming evidence was available, so a de novo origin cannot be established.
PS3Not assessed: no functional or biochemical assay data specific to p.(Arg162Cys) was available.
PS4Not assessed: no case-control data or variant-specific enrichment analysis for c.484C>T was provided.
PM1Not assessed: no curated hotspot/domain definition is available, and cancerhotspots.org does not list this position as a statistically significant hotspot.
PM3Not assessed: no affected-proband data places this variant in trans with a pathogenic CHEK1 variant.
PM5Not assessed: no established pathogenic missense variant at codon 162 was identified.
PM6Not assessed: no parental testing result is present, so a presumed de novo occurrence cannot be determined.
PP1Not assessed: no family segregation data or informative meioses were available.
PP2Not assessed: no CHEK1-specific guidance or missense-constraint data establishes missense as a common disease mechanism.
PP3Not met: REVEL score 0.437 falls within the gray zone (0.250-0.750), providing no in-silico support for pathogenicity.
PP4Not assessed: no proband phenotype indicating a CHEK1-specific presentation was provided.
PP5Not met: the exact variant has no ClinVar record, so no expert-panel pathogenic assertion exists.
Benign
BA1Not met: highest population frequency is 0.00450% (East Asian), far below the 1% BA1 threshold.
BS1Not met: highest ancestry-specific frequency is 0.00450%, below the 0.3% BS1 benign threshold.
BS2Not assessed: no phenotype-confirmed healthy adult carriers were documented; sparse heterozygous observations alone are insufficient.
BS3Not assessed: no variant-specific functional assay data for p.(Arg162Cys) was available to demonstrate normal function.
BS4Not assessed: no genotype-positive unaffected or genotype-negative affected relatives were documented.
BP1Not assessed: no quantitative data confirms that missense variants are not a common cause of CHEK1 disease.
BP2Not assessed: no phase or pedigree data places this variant in cis or trans with a pathogenic CHEK1 variant.
BP4Not met: REVEL score 0.437 is above the <0.250 BP4 threshold required for benign in-silico support.
BP5Not assessed: no alternate molecular diagnosis providing another basis for disease was documented.
BP6Not met: the exact variant has no ClinVar record, so no expert-panel benign assertion exists.
N/A · 4PVS1 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24661e-05; MAF= 0.00125%, 20/1604350 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.49519e-05; MAF= 0.00450%, 2/44492 alleles, homozygotes = 0); grpmax FAF= 8.8e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.24068e-05; MAF= 0.00124%, 3/241802 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.20328e-05; MAF= 0.00320%, 1/31218 alleles, homozygotes = 0); grpmax FAF= 2.98e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0012%
· 20 / 1,604,350
0 hom · FAF 0.00088%
East Asian
2 / 44,492
0.0045%
Admixed American
1 / 57,182
0.0017%
European (non-Finnish)
17 / 1,177,406
0.0014%
+ 7 not observed (Remaining individuals, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 241,802
0 hom · FAF 0.0003%
Admixed American
1 / 31,218
0.0032%
European (non-Finnish)
2 / 111,286
0.0018%
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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.
