LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-08
Case ID: NM_007194.4_c.1561C_T_20261008_164019
Framework: ACMG/AMP 2015
Variant classification summary

NM_007194.4:c.1561C>T

CHEK2  · NP_009125.1:p.(Arg521Trp)  · NM_007194.4
GRCh37: chr22:29083956 G>A  ·  GRCh38: chr22:28687968 G>A
Gene: CHEK2 Transcript: NM_007194.4
Final call
Likely Benign
BP1 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
CHEK2
Transcript
NM_007194.4
Protein
NP_009125.1:p.(Arg521Trp)
gnomAD AF
4.511306461819936e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BP1 (supporting) is met because this missense change lies in CHEK2, a gene where disease is caused predominantly by protein-truncating variants.
2
Likely Benign: BP4 (supporting) is met because REVEL 0.205 is at or below the ClinGen SVI supporting threshold for a benign protein impact.
3
No pathogenic criterion is met, so the two supporting benign criteria combine to a Likely Benign call.
Final determination: Under the generic ACMG/AMP 2015 combination rules, two supporting benign criteria (BP1 + BP4) map to Likely Benign.
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 PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_007194.4:c.1561C>T in CHEK2 is a missense substitution predicted to produce NP_009125.1:p.(Arg521Trp). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: p.Arg521Trp (ClinVar 140881) is classified Uncertain significance by all submitters, so it is not an established pathogenic same-amino-acid change.
clinvar pm5_candidates generic_acmg_combination_rules cspec
PS2 Not assessed Not assessed: no proband or parental genotype data exist to establish a de novo occurrence for c.1561C>T.
cspec clinvar PMID:25741868
PS3 Not met Not met: the yeast assay scored p.Arg521Trp as benign while mouse-ES and ENIGMA assays showed only intermediate kinase or mislocalization effects, a conflict precluding a damaging-effect call.
PMID:37449874 PMID:34903604 PMID:30851065 generic_acmg_combination_rules cspec
PS4 Not met Not met: no variant-specific case-control odds ratio for p.Arg521Trp, only a class-level OR 2.83 for functionally impaired CHEK2 variants.
PMID:37449874 PMID:25741868
PM1 Not met Not met: no VCEP domain table or approved CHEK2 critical-domain list exists and CancerHotspots shows residue 521 is not a statistically significant hotspot.
cspec PMID:37449874 gnomad_v2 generic_acmg_combination_rules
PM2 Not met Not met: gnomAD v4.1 East Asian popmax FAF 0.0004053 (v2.1 0.00022085) exceeds the 0.0001 PM2 threshold despite a globally rare AF of 4.5e-05.
gnomad_v2 gnomad_v4 gnomad_canada cspec PMID:25741868
PM3 N/A Not applicable: CHEK2-related cancer predisposition is autosomal dominant, so PM3's recessive, in-trans requirement cannot apply to this single heterozygous missense variant.
cspec final_classification_framework PMID:25741868 clinvar
PM4 N/A PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_007194.4:c.1561C>T in CHEK2 is a missense substitution predicted to produce NP_009125.1:p.(Arg521Trp). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: no established pathogenic missense exists at codon 521; R521Q (PMID:37449874) is only functionally impaired, not classified pathogenic.
pm5_candidates clinvar PMID:37449874 generic_acmg_combination_rules
PM6 Not assessed Not assessed: no proband exists in whom an assumed (unconfirmed) de novo occurrence of c.1561C>T could be recorded.
cspec clinvar PMID:25741868
PP1 Not assessed Not assessed: no pedigree or relative genotypes were provided, and the cited segregation paper (PMID:32973888) does not mention the variant.
cspec clinvar PMID:25741868 PMID:32973888
PP2 Not met Not met: CHEK2 disease is caused predominantly by truncating alleles, and PMID:18163131 states only a small proportion are missense, so missense is not a common mechanism.
PMID:18163131 generic_acmg_combination_rules cspec
PP3 Not met Not met: REVEL 0.205 for this missense variant is below the >=0.644 ClinGen SVI supporting PP3 threshold.
revel cspec
PP4 Not met Not met: the CHEK2 cancer-predisposition phenotype is not highly specific to a single gene and no proband-level phenotypic data supports PP4.
PMID:25741868 PMID:18163131
PP5 Not met Not met: ClinVar has no expert-panel classification for this variant; the record is Uncertain significance (2-star, 0 expert-panel submissions).
clinvar PMID:25741868
BA1 Not met Not met: highest observed population frequency (gnomAD v4.1 East Asian popmax FAF 0.0004053) is over 120-fold below the 0.05 BA1 threshold.
gnomad_v2 gnomad_v4 cspec PMID:25741868
BS1 Not met Not met: highest observed population frequency (gnomAD v4.1 East Asian popmax FAF 0.0004053) is about 25-fold below the 0.01 BS1 threshold.
gnomad_v2 gnomad_v4 cspec PMID:25741868
BS2 N/A Not applicable: CHEK2-related cancer predisposition is adult-onset and incompletely penetrant, and all gnomAD subsets report zero homozygotes (v2.1, v4.1).
gnomad_v2 gnomad_v4 gnomad_canada cspec
BS3 Not met Not met: the yeast assay's wild-type-like growth is contradicted by an intermediate mouse-ES kinase defect and ENIGMA's impaired-localization classification of p.R521W.
PMID:30851065 PMID:34903604 PMID:37449874 generic_acmg_combination_rules cspec
BS4 Not assessed Not assessed: no family segregation or non-segregation data were provided for c.1561C>T.
cspec clinvar PMID:25741868 PMID:32973888
BP1 Met Met (supporting): CHEK2 disease is caused primarily by truncating variants (PMID:18163131) and p.Arg521Trp is a missense change.
PMID:18163131 PMID:37449874 generic_acmg_combination_rules cspec
BP2 Not met Not met: neither a trans nor a cis configuration with a pathogenic CHEK2 allele was observed for this variant.
cspec final_classification_framework PMID:25741868 PMID:18163131 clinvar PMID:37449874
BP3 N/A BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_007194.4:c.1561C>T in CHEK2 is a missense substitution predicted to produce NP_009125.1:p.(Arg521Trp). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Met Met at supporting: REVEL 0.205 is at or below the <=0.29 ClinGen SVI BP4 supporting threshold.
revel cspec
BP5 Not assessed Not assessed: no proband/case-level data are available to determine whether an alternate molecular basis for disease exists.
PMID:25741868
BP6 Not met Not met: ClinVar shows Uncertain significance with 0 expert-panel submissions and no benign classification for this variant.
clinvar PMID:25741868
BP7 N/A BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_007194.4:c.1561C>T in CHEK2 is a missense substitution predicted to produce NP_009125.1:p.(Arg521Trp). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
generic_acmg_combination_rules
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.