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.1 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.2 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.3 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).4
CHEK1
Final classification
VUS
CHEK1 c.1148A>T · p.Lys383Ile
CHEK1
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.
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.
Classification rationale
PM2
VUS
CHEK1 c.1148A>T
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001274.5 · variants mapped to exon structure
CHEK1
NM_001274.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from all gnomAD population databases (v2.1v4.1Canada).
Assessed · not applied
Pathogenic
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.
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.
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.
PS4
No case-control study or cohort analysis demonstrates enrichment of this variant in affected individuals compared to controls.
PM1
The variant lies in the C-terminal regulatory domain (residues ~266-476), outside the protein kinase domain (residues 10-265).
PM6
No de novo event with confirmed maternity and paternity has been reported for this variant in any database or publication.
PP1
No co-segregation data are available for this variant.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
In silico predictors do not provide multiple consistent lines of evidence supporting a deleterious effect.
PP4
PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5
No reputable clinical diagnostic laboratory or expert panel has classified this variant as pathogenic.
Benign
BA1
BA1 requires allele frequency >1% in population databases.
BS1
BS1 requires allele frequency >0.3% in population databases for non-VCEP assessment.
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.
BS3
No functional study has demonstrated that p.Lys383Ile does not alter CHEK1 protein function in a validated assay.
BS4
No family studies demonstrating lack of segregation with disease are available for this variant.
BP1
BP1 requires that a missense variant occurs in a gene where only truncating variants are known to cause disease.
BP2
BP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder.
BP4
In silico predictors show discordant results.
BP5
BP5 requires that the variant is found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to classify the variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links