NM_001274.5:c.157A>G

CHEK1 · NP_001265.2:p.(Lys53Glu) · NM_001274.5

GRCh37: chr11:125497593 A>G · GRCh38: chr11:125627698 A>G

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Lys53Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001274.5:c.157A>G (p.Lys53Glu) in CHEK1 is a missense variant absent from all gnomAD population databases (v2.1, v4.1, Canada), meeting PM2 at supporting strength.

No pathogenic or likely pathogenic variant has been reported at the same amino acid residue (Lys53) in ClinVar; PS1 and PM5 are not applicable.

Multiple lines of in silico evidence do not support a deleterious effect: REVEL 0.271, BayesDel -0.154, SpliceAI max delta 0.00. PP3 is not met.

PVS1 is not applicable as this is a missense variant not falling into null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798).

No functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control data (PS4), phenotype data (PP4), or ClinVar classifications (PS5/PP5/BP6) are available for this variant.

With PM2_supporting as the sole met criterion, the variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 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	N/A	NM_001274.5:c.157A>G is a missense variant (p.Lys53Glu) and does not fall into the null-variant buckets (nonsense, frameshift, canonical ±1,2 splice) required for generic PVS1 application under PMC6185798.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No pathogenic variant with a different amino acid substitution at the same residue (Lys53) has been identified. PM5 candidate search returned zero same-residue comparator variants in ClinVar.	pm5_candidates
PS2	N/A	No de novo observation data available. No ClinVar submissions, no literature reports, and no family studies documenting de novo occurrence of this variant.
PS3	Not assessed	No well-established functional studies evaluate the specific variant NM_001274.5:c.157A>G. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No COSMIC data.	oncokb
PS4	Not assessed	No case-control or cohort studies include this variant. Absent from ClinVar and COSMIC. The variant has not been reported in affected individuals relative to controls.
PS5	Not assessed	No ClinVar submissions exist for this variant. No alternative-source pathogenic classification is available for evaluation.	clinvar
PM1	Not assessed	Position 53 lies within the CHEK1 kinase domain (residues ~1-265), but no VCEP/CSPEC defines this residue as a mutational hotspot or critical functional domain position. Cancer Hotspots analysis found no statistically significant hotspot at this residue.
PM2	Met	NM_001274.5:c.157A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0 in all populations (<0.1% threshold).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with alternative pathogenic substitutions identified at Lys53. PM5 candidate search returned zero candidates.	pm5_candidates
PM6	N/A	No de novo observation reported. No family data or trio testing results available for this variant.
PP1	Not assessed	No segregation data available. No family studies or co-segregation analyses include this variant.
PP2	Not assessed	HCI prior data not available for CHEK1. Cannot determine whether the gene has a low rate of benign missense variation. Without HCI prior or CSPEC specification, PP2 cannot be applied.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.271 (<0.5 threshold), BayesDel score -0.154 (<0.27 threshold), and SpliceAI max delta 0.00 (no splice impact) all indicate a neutral or benign in silico profile.	revel bayesdel spliceai
PP4	Not assessed	No phenotype data available. The variant has not been identified in patients with CHEK1-related disease phenotypes in ClinVar or published literature.
PP5	Not assessed	No reputable source has classified this variant as pathogenic. No ClinVar submissions exist, and no expert panel has evaluated this variant.	clinvar
BA1	Not met	Variant is absent from all gnomAD populations (AF=0). Does not meet the BA1 threshold of >1% allele frequency.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from all gnomAD populations (AF=0). Does not meet the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observations in healthy adult controls or homozygous state available. No individual-level data to evaluate BS2.
BS3	Not assessed	No well-established functional studies have evaluated the specific effect of p.Lys53Glu on CHEK1 protein function. In silico predictors suggest neutral effect but do not constitute BS3-level functional evidence.
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	Not assessed	Although CHEK1 loss-of-function is a supported disease mechanism with truncating variants implicated (PMID:38686193), insufficient evidence exists to determine that primarily truncating variants cause CHEK1-related disease such that a missense change should be downgraded. No CSPEC/VCEP specification available.
BP2	Not assessed	No phase information available. No observations in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4	Not met	Computational evidence is mixed and does not meet the 'multiple lines suggesting no impact' threshold. REVEL 0.271 and SpliceAI 0.00 suggest no impact, but BayesDel -0.154 is intermediate and does not provide a clear benign prediction.	revel bayesdel spliceai
BP5	N/A	No observations of this variant in a case with an alternate molecular basis for disease.
BP6	N/A	No reputable source has reported this variant as benign. No ClinVar submissions or literature classifications exist.
BP7	N/A	BP7 applies to synonymous variants. NM_001274.5:c.157A>G is a missense variant (p.Lys53Glu), not synonymous.

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