NM_001274.5:c.1070G>A

CHEK1 · NP_001265.2:p.(Ser357Asn) · NM_001274.5

GRCh37: chr11:125514132 G>A · GRCh38: chr11:125644237 G>A

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Ser357Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant in CHEK1 (c.1070G>A, p.Ser357Asn) is absent from gnomAD population databases (PM2_Supporting).

Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303, and SpliceAI max delta 0.03 indicates no splice impact (BP4_Supporting).

The variant is absent from ClinVar and COSMIC; no experimental functional data, segregation data, or de novo reports were identified.

One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met; these cancel and no pathogenic or benign combination is reached per the generic ACMG/AMP 2015 classification framework. 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	Missense variant (c.1070G>A, p.Ser357Asn) does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic variant with the same amino acid change (p.Ser357Asn) has been reported in ClinVar. This variant is entirely absent from ClinVar.	clinvar
PS2	Not met	No de novo report with confirmed paternity and maternity was identified for this variant.
PS3	Not met	No variant-specific functional data identified. OncoKB reports Unknown Oncogenic Effect. No published experimental studies test c.1070G>A or a systematically characterized range that includes residue S357.	oncokb
PS4	Not met	No case-control studies, odds ratio data, or statistical enrichment evidence available for this variant.
PS5	Not met	Variant is absent from ClinVar; no expert panel or reputable source has classified this variant as pathogenic.	clinvar
PM1	Not met	Residue S357 lies in the C-terminal regulatory domain of CHEK1, outside the well-characterized kinase domain (residues ~1-265). Cancerhotspots.org does not identify this position as a statistically significant hotspot. No literature evidence defines S357 as a critical functional domain residue.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (genomes/exomes), meeting the PM2 threshold of <0.1% population allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense comparator at the same residue (S357) identified in ClinVar. PM5 candidate search returned no candidates.	pm5_candidates clinvar
PM6	Not met	No de novo report was identified for this variant. No confirmed de novo occurrence with parental testing data available.
PP1	Not met	No segregation data available for this variant. Cosegregation with disease in affected family members cannot be assessed.
PP2	Not met	No HCI prior score or gene-specific missense constraint data available for CHEK1. Low rate of benign missense variation cannot be established without these data.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.167 (well below pathogenic threshold of 0.5), BayesDel score -0.303 (negative/benign), SpliceAI max delta 0.03 (no predicted splice impact). Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data provided to assess specificity for CHEK1-related hereditary cancer predisposition.
PP5	Not met	Variant is absent from ClinVar; no reputable source has classified this variant. No expert panel classification exists to support pathogenicity.	clinvar
BA1	Not met	Variant is absent from gnomAD; does not meet the BA1 threshold of >1% allele frequency in any population.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD; does not meet the BS1 threshold of >0.3% allele frequency in population databases.	gnomad_v2 gnomad_v4
BS2	Not met	Variant is absent from population databases; no evidence of observation in healthy adults to support BS2.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a neutral or benign effect for this variant. In silico scores (REVEL 0.167, BayesDel -0.303) are weakly benign but do not constitute functional data sufficient for BS3.	revel bayesdel
BS4	Not met	No segregation data showing lack of cosegregation with disease. No family-based evidence available to support BS4.
BP1	Not met	BP1 applies to truncating variants in genes where only truncating variants cause disease. This is a missense variant, and CHEK1 missense variants have been reported in the germline literature as potentially pathogenic, so BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a known pathogenic CHEK1 variant. Variant is absent from population databases, precluding assessment of phase with other variants.	gnomad_v2 gnomad_v4
BP4	Met	Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303 (negative/benign), and SpliceAI max delta score 0.03 indicates no significant splice impact. Computational evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No case-level data showing an alternate molecular basis for disease in an individual harboring this variant.
BP6	Not met	Variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.1070G>A, p.Ser357Asn), not a synonymous variant. BP7 is reserved for synonymous variants with no predicted splice impact.

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