NM_001274.5:c.922A>T

CHEK1 · NP_001265.2:p.(Ser308Cys) · NM_001274.5

GRCh37: chr11:125513794 A>T · GRCh38: chr11:125643899 A>T

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Ser308Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001274.5:c.922A>T (p.Ser308Cys) is a missense variant in CHEK1 that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

Multiple in silico predictors (REVEL 0.059, BayesDel -0.329, SpliceAI max delta 0.00) consistently predict no deleterious effect, meeting BP4 at supporting benign strength.

The variant is absent from ClinVar with no prior classifications, and no variant-specific functional or clinical publications were identified.

The PVS1 null-variant framework does not apply to this missense substitution; no truncation, frameshift, or canonical splice disruption is predicted.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, resulting in a variant of uncertain significance (VUS) per generic ACMG/AMP 2015 combination rules.

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	Not met	NM_001274.5:c.922A>T is a missense variant (p.Ser308Cys) that does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternate nucleotide change at c.922 resulting in the same amino acid (p.Ser308Cys) has been established as pathogenic; the variant is absent from ClinVar and no comparator variants were identified.	clinvar pm5_candidates
PS2	Not assessed	De novo status cannot be evaluated; no proband or parental genotype data are available.
PS3	Not met	No variant-specific functional studies were identified in the literature; OncoKB reports unknown oncogenic effect and the variant is absent from COSMIC.	oncokb
PS4	Not assessed	No case-control or cohort prevalence data are available to evaluate enrichment in affected individuals.
PS5	Not met	No reputable source has recently reported this variant as pathogenic with evidence not available for independent evaluation.	clinvar
PM1	Not met	p.Ser308Cys does not lie in a statistically significant mutational hotspot per cancerhotspots.org and no domain-level functional characterization specific to this residue in CHEK1 was identified.
PM2	Met	NM_001274.5:c.922A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population (allele frequency well below 0.1% threshold).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at codon 308 with a different amino acid change was identified in ClinVar; zero same-residue comparator candidates were found.	pm5_candidates clinvar
PM6	Not assessed	Assumed de novo status cannot be evaluated; no proband or parental genotype data are available.
PP1	Not assessed	No family segregation data are available to evaluate co-segregation with disease.
PP2	Not met	HCI prior probability of pathogenicity data are not available for CHEK1; cannot establish that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism.
PP3	Not met	Multiple in silico predictors uniformly suggest a benign effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00. These scores do not support a deleterious prediction.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to evaluate specificity for a disease with single genetic etiology.
PP5	Not met	The variant is absent from ClinVar; no reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from all gnomAD datasets (v2.1, v4.1, Canada); allele frequency is 0%, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD datasets; allele frequency is 0%, below the 0.3% BS1 threshold for a benign allele frequency observation.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation in healthy adults for a disorder expected to have full penetrance at an early age.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect of p.Ser308Cys were identified in the literature.
BS4	Not assessed	No family segregation data are available to evaluate lack of segregation with disease.
BP1	Not met	Although CHEK1 loss of function is a supported germline disease mechanism, insufficient evidence exists to establish that truncating variants are the sole or predominant cause of disease while missense variants are not pathogenic.	pvs1_gene_context
BP2	Not assessed	No data on observation in trans with a pathogenic dominant variant are available.
BP3	N/A	Variant is a missense substitution; BP3 applies only to in-frame insertions/deletions in repetitive regions.
BP4	Met	Multiple in silico predictors consistently predict no deleterious effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00, supporting a benign interpretation.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in this case.
BP6	Not met	The variant is absent from ClinVar; no reputable source has classified this variant as benign.	clinvar
BP7	Not met	NM_001274.5:c.922A>T is a missense variant (p.Ser308Cys), not synonymous; BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
PM3	N/A	No proband data available; requires observation in trans with a pathogenic variant.
PM4	N/A	Variant is a missense substitution; PM4 applies only to protein length-changing variants (stop-loss, in-frame indels).

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