LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-10
Case ID: NM_007194.4_c.1420C_T_20261110_143931
Framework: ACMG/AMP 2015
Variant classification summary

NM_007194.4:c.1420C>T

CHEK2  · NP_009125.1:p.(Arg474Cys)  · NM_007194.4
GRCh37: chr22:29090061 G>A  ·  GRCh38: chr22:28694073 G>A
Gene: CHEK2 Transcript: NM_007194.4
Final call
Likely Pathogenic
PS3 strong PP3 moderate PM2 supporting PP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
CHEK2
Transcript
NM_007194.4
Protein
NP_009125.1:p.(Arg474Cys)
gnomAD AF
2.005075346972023e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong from two orthogonal variant-specific functional assays showing impaired CHEK2 function.
2
Likely Pathogenic: PP3 moderate from a REVEL score of 0.903 meeting the calibrated moderate threshold.
3
Likely Pathogenic: PM2 supporting from an extremely rare gnomAD v4.1 allele frequency with no homozygotes.
4
Likely Pathogenic: PP1 supporting from the exact variant occurring in two affected siblings from one family.
Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong pathogenic criterion plus 1 moderate and 2 supporting pathogenic criteria yields Likely Pathogenic.
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 Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: p.Arg474Cys is reported, but no independently established pathogenic same-amino-acid change from a different nucleotide substitution is documented.
PMID:27900359
PS2 Not assessed Not assessed: no documented proband-specific de novo event with both maternity and paternity confirmed and no family history.
PS3 Met Met, strong: two orthogonal variant-specific assays showed impaired CHEK2 activation or DNA-damage survival, including three independent yeast experiments with four to six replicates each.
PMID:27900359 PMID:30851065
PS4 Not met Not met: no exact-variant affected-versus-control comparison provides an odds ratio or relative risk >5.0 with a confidence interval excluding 1.0.
PMID:27900359 PMID:30269267 PMID:26094658
PM1 Not assessed Not assessed: p.Arg474Cys lies in the kinase domain, but benign variation across that domain and a qualifying hotspot are not established.
PMID:30851065 PMID:26094658 hotspots
PM2 Met Met at supporting: gnomAD v4.1 AF is 2.00508e-05, below the generic PM2 threshold of 0.0001, with zero homozygotes.
gnomad_v2 gnomad_v4 cspec PMID:25741868
PM3 N/A Not applicable: CHEK2-related cancer predisposition is autosomal dominant, while PM3 requires a recessive disorder and a pathogenic variant in trans.
final_classification_framework PMID:27900359
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no different missense substitution at CHEK2 Arg474 determined to be pathogenic is documented.
PM6 Not assessed Not assessed: no documented assumed de novo occurrence in the proband without parental confirmation.
PP1 Met Met at supporting strength: the exact variant was homozygous in two affected siblings with multiple primary cancers from one family.
PMID:27900359
PP2 Not assessed Not assessed: CHEK2-specific evidence for both low benign missense variation and a common missense disease mechanism is unavailable.
PP3 Met Met at moderate strength: missense REVEL score 0.903 meets the >= 0.773 PP3 threshold but not the >= 0.932 strong threshold.
revel
PP4 Not met Not met: reported lung, breast, prostate, colon, and thyroid cancers are heterogeneous and not highly specific for a single genetic etiology.
PMID:27900359 PMID:30269267
PP5 Not met Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification; available assertions are non-expert submissions.
clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 1.568e-05, far below the generic BA1 threshold of 0.05.
gnomad_v2 gnomad_v4 cspec
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 1.568e-05, approximately 638-fold below the generic BS1 threshold of 0.01.
gnomad_v2 gnomad_v4 cspec
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes, but no eligible healthy adult carrier observation with age and phenotype context is documented.
gnomad_v2 gnomad_v4 PMID:27900359
BS3 Not met Not met: variant-specific cell and yeast assays showed reduced CHEK2 activation or DNA-damage survival rather than no damaging effect.
PMID:27900359 PMID:30851065
BS4 Not assessed Not assessed: no affected relative is documented as lacking the variant, and broader family testing is unavailable.
PMID:27900359
BP1 Not assessed Not assessed: CHEK2 loss-of-function disease evidence does not establish that disease is caused primarily by truncating variants.
BP2 Not assessed Not assessed: no phase-resolved observation with a different pathogenic variant is documented, so cis/trans status required for BP2 is unavailable.
final_classification_framework PMID:27900359
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: missense REVEL score 0.903 exceeds the <= 0.29 BP4 supporting threshold, so it does not support a tolerated effect.
revel
BP5 Not met Not met: no reviewed case carrying the variant has a documented alternate molecular basis that explains the disease.
PMID:27900359 PMID:30269267
BP6 Not met Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification to support BP6.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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