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.1 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.2 The variant is absent from ClinVar with no prior classifications, and no variant-specific functional or clinical publications were identified.3 The PVS1 null-variant framework does not apply to this missense substitution; no truncation, frameshift, or canonical splice disruption is predicted.4 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.5
CHEK1
Final classification
VUS
CHEK1 c.922A>T · p.Ser308Cys
CHEK1
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.
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.
Classification rationale
PM2
BP4
VUS
CHEK1 c.922A>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
pvs1_generic_framework ↗pvs1_variant_assessment
5
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 · 2 applied · 23 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: absentgnomAD v4.1: absentgnomAD-Canada v1.0: AC=0
✓
BP4
supporting
Benign
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: 0.059 (benign-leaning)BayesDel: -0.329 (benign-leaning)SpliceAI: max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PVS1
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.
PS1
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.
PS2
De novo status cannot be evaluated; no proband or parental genotype data are available.
PS3
No variant-specific functional studies were identified in the literature; OncoKB reports unknown oncogenic effect and the variant is absent from COSMIC.
PS4
No case-control or cohort prevalence data are available to evaluate enrichment in affected individuals.
PM1
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.
PM5
No pathogenic missense variant at codon 308 with a different amino acid change was identified in ClinVar; zero same-residue comparator candidates were found.
PM6
Assumed de novo status cannot be evaluated; no proband or parental genotype data are available.
PP1
No family segregation data are available to evaluate co-segregation with disease.
PP2
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
Multiple in silico predictors uniformly suggest a benign effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00.
PP4
No patient phenotype or family history data are available to evaluate specificity for a disease with single genetic etiology.
PP5
The variant is absent from ClinVar; no reputable source has classified this variant as pathogenic.
Benign
BA1
The variant is absent from all gnomAD datasets (v2.1, v4.1, Canada); allele frequency is 0%, well below the 1% BA1 threshold.
BS1
The variant is absent from all gnomAD datasets; allele frequency is 0%, below the 0.3% BS1 threshold for a benign allele frequency observation.
BS2
No data are available regarding observation in healthy adults for a disorder expected to have full penetrance at an early age.
BS3
No well-established functional studies demonstrating no deleterious effect of p.Ser308Cys were identified in the literature.
BS4
No family segregation data are available to evaluate lack of segregation with disease.
BP1
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.
BP2
No data on observation in trans with a pathogenic dominant variant are available.
BP5
No data are available regarding an alternate molecular basis for disease in this case.
BP6
The variant is absent from ClinVar; no reputable source has classified this variant as benign.
BP7
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.
N/A · 3
PM3 · PM4 · BP3
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 = 0.00). REVEL score = 0.059. BayesDel score = -0.329077.
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