LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-27
Case ID: NM_007194.4_c.1604G_A_20260727_191603
Framework: ACMG/AMP 2015
Variant classification summary

CHEK2  · NP_009125.1:p.(Arg535His)  · NM_007194.4
GRCh37: chr22:29083913 C>T  ·  GRCh38: chr22:28687925 C>T
Gene: CHEK2 Transcript: NM_007194.4
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
CHEK2
Transcript
NM_007194.4
Protein
NP_009125.1:p.(Arg535His)
gnomAD AF
9.15909473013292e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_007194.4:c.1604G>A (p.Arg535His) is a missense variant in CHEK2 located in the C-terminal region of the protein, outside the kinase and FHA domains.
2
Multiple independent computational predictors (REVEL 0.046, BayesDel -0.342, SpliceAI delta 0.00, SIFT Tolerated, Align GVGD C0, MutationTaster Polymorphism) converge on a benign interpretation, satisfying BP4 at supporting benign strength.
3
Direct functional assessment in a yeast-based assay (Delimitsou et al. 2019, PMID:30851065) characterized this variant as benign (wild-type-like function), consistent with the computational predictions.
4
The variant is present in gnomAD population databases (v2.1: 63/264,906 alleles, AF=0.024%, grpmax FAF=0.16%, 1 homozygote; v4.1: 146/1,594,044 alleles, AF=0.0092%, grpmax FAF=0.11%, 2 homozygotes) with highest frequency in the South Asian subpopulation (0.20% v2.1).
5
In ClinVar (VariationID 128067), this variant has received a mixed classification: Likely benign by 8 clinical laboratories, Uncertain significance by 6, and Benign by 1. Review status is single-submitter (1-star) rather than expert panel.
6
No pathogenic ACMG/AMP criteria are met. No benign criteria are met beyond BP4 (supporting benign). The evidence is insufficient for a definitive benign classification; the variant remains a variant of uncertain significance (VUS), leaning benign based on computational and functional data.
Final determination:
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; not a null variant (nonsense, frameshift, or canonical splice). PVS1 variant assessment bucket is 'other'. Does not qualify for PVS1 under generic or VCEP framework.
pvs1_gene_context pvs1_variant_assessment
PS1 N/A No prior classification establishing this same amino acid change (p.Arg535His) as pathogenic at another nucleotide position exists. PS1 requires a different nucleotide change resulting in the same amino acid alteration that has been previously classified as pathogenic.
PS2 N/A No de novo data reported for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed.
PS3 Not met The variant was directly tested in a yeast-based functional assay (PMID:30851065) and categorized as BENIGN (wild-type-like function). In silico predictions are concordant: SIFT tolerated, Align GVGD C0, MutationTaster polymorphism (0.999). PolyPhen-2 predicted probably damaging (discordant). No other functional studies tested this variant. A benign functional result does not support PS3; the evidence is more consistent with a benign interpretation.
PMID:30851065
PS4 N/A No case-control data demonstrating statistically significant enrichment of this variant in affected individuals versus controls. PS4 requires disease-specific case-control data for the variant.
PS5 N/A No established pathogenic variant at this codon (Arg535) has been identified as a comparator. The ClinVar submission referenced in criterion_lead does not establish PS5.
PM1 Not met Residue Arg535 is located in the C-terminal region outside the characterized kinase domain (aa 220-486) and FHA domain (aa 115-175). The domain annotation in PMID:30851065 lists it as '-' (no specific functional domain). Cancerhotspots.org does not identify this residue as a significant hotspot. The C-terminal region including the NLS (aa 515-522) is not a well-established mutational hotspot.
PMID:30851065
PM2 Not met This variant is present in gnomAD v2.1 at a global frequency of 0.024% (63/264,906 alleles, 1 homozygote) and v4.1 at 0.0092% (146/1,594,044 alleles, 2 homozygotes). The grpmax filtering allele frequency is 0.16% (v2.1) and 0.11% (v4.1), both exceeding the 0.1% threshold for PM2. The highest subpopulation frequency is in South Asian (v2.1 AF=0.20%, v4.1 AF=0.13%). Presence in population databases with a homozygous individual precludes application of PM2.
gnomad_v2 gnomad_v4
PM5 N/A No same-residue comparator variants with established pathogenic classification were identified. PM5 candidate collection was unable to confirm classic same-residue PM5 semantics.
pm5_candidates
PM6 N/A No de novo data reported for this variant. PM6 requires confirmed de novo occurrence without maternity/paternity confirmation (supporting) or with it (moderate).
PP1 N/A No segregation data available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2 Not met CHEK2 has a high rate of benign missense variation (1.87% missense variants in gnomAD). The gene does not have a low rate of benign missense variation, which is a prerequisite for PP2.
PMID:37449874
PP3 Not met Computational evidence supports a benign interpretation. REVEL score is 0.046 (below the 0.5 threshold for pathogenicity). BayesDel score is -0.342 (negative, supporting benign). SpliceAI max delta is 0.00 (no predicted splice impact). Multiple in silico tools predict no damaging effect. The yeast functional assay (PMID:30851065) also found the variant to be benign.
revel bayesdel spliceai PMID:30851065
PP4 N/A No phenotype specificity data available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5 Not met ClinVar classification is 'Likely benign' (8 clinical labs) with 'Uncertain significance' (6 labs) and 'Benign' (1 lab). Review status is 'criteria provided, single submitter' (1-star). PP5 requires a reputable source (3-star expert panel) classifying the variant as pathogenic. The ClinVar review status is single-submitter, not expert panel level. Additionally, the predominant classification is benign-leaning, which would support BP6 rather than PP5.
clinvar
BA1 Not met The highest population allele frequency is 0.20% in the South Asian subpopulation (gnomAD v2.1), which is well below the 1% threshold for BA1.
gnomad_v2 gnomad_v4
BS1 Not met The global allele frequency is 0.024% (v2.1) and 0.0092% (v4.1), both below the 0.3% threshold for BS1. The highest subpopulation frequency in South Asians (0.20% v2.1) also remains below the BS1 cutoff.
gnomad_v2 gnomad_v4
BS2 Not met Only 1 homozygous individual is observed in gnomAD v2.1 (in the South Asian population). BS2 generally requires observation in multiple healthy adult homozygous individuals for a fully penetrant dominant disorder. A single homozygote is not sufficient to meet BS2.
gnomad_v2
BS3 Not met A single yeast-based functional study (PMID:30851065) characterized this variant as benign. While this is direct functional evidence of no damaging effect, BS3 requires 'well-established' functional studies (typically replicated in multiple independent studies or using multiple orthogonal assays). A single yeast assay, with one discordant in silico prediction (PolyPhen-2: probably damaging), does not rise to the level of 'well-established.' The functional data is considered supportive but does not independently meet BS3.
PMID:30851065
BS4 N/A No segregation data available. BS4 requires lack of segregation with disease in multiple affected family members.
BP1 N/A This is a missense variant, not a truncating variant in a gene where only truncating variants cause disease. BP1 applies specifically to missense variants in genes where truncation is the only known pathogenic mechanism.
BP2 Not met No evidence of co-occurrence with a known pathogenic variant in trans for a fully penetrant dominant disorder. No data on co-occurrence in cis with a pathogenic variant.
BP4 Met Multiple independent lines of computational evidence predict no damaging effect: REVEL score 0.046 (below the default 0.5 pathogenicity threshold), BayesDel score -0.342 (negative, strongly supporting benign), SpliceAI max delta 0.00 (no predicted splice alteration), and in silico tools from PMID:30851065 (SIFT: Tolerated, Align GVGD: C0, MutationTaster: Polymorphism). Four independent predictors converge on a benign interpretation.
revel bayesdel spliceai PMID:30851065
BP5 Not met No evidence that this variant was found in a case with an alternate molecular basis for disease. BP5 requires identification of an alternate pathogenic variant that explains the phenotype.
BP6 Not met ClinVar review status is 'criteria provided, single submitter' (1-star), not expert panel (3-star) review. Per ClinGen CSPEC guidance, only 3-star expert panel classifications trigger automatic PP5/BP6 application. The overall ClinVar classification is 'Likely benign' but the review status does not meet the threshold for BP6.
clinvar
BP7 N/A BP7 applies only to synonymous (silent) variants with no predicted splice impact. This variant (c.1604G>A) is a missense substitution resulting in p.Arg535His.
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