NM_001274.5:c.1148A>T

CHEK1 · NP_001265.2:p.(Lys383Ile) · NM_001274.5

GRCh37: chr11:125514453 A>T · GRCh38: chr11:125644558 A>T

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Lys383Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	No de novo occurrence of NM_001274.5:c.1148A>T has been reported in any database or publication, with or without confirmed parentage.	clinvar
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	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.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	No de novo event with confirmed maternity and paternity has been reported for this variant in any database or publication.
PP1	Not met	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.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	No reputable clinical diagnostic laboratory or expert panel has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in population databases. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires allele frequency >0.3% in population databases for non-VCEP assessment. This variant is absent from all gnomAD datasets.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.
BS4	Not met	No family studies demonstrating lack of segregation with disease are available for this variant.
BP1	Not met	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.
BP2	Not met	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.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single nucleotide substitution.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a missense substitution (p.Lys383Ile), not a synonymous variant.
PM3	N/A	PM3 applies to recessive disorders. CHEK1 is not associated with a recessive disease, and no reports of biallelic CHEK1 variants exist.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a single nucleotide missense substitution.

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