NM_001274.5:c.965G>A

CHEK1 · NP_001265.2:p.(Arg322His) · NM_001274.5

GRCh37: chr11:125514027 G>A · GRCh38: chr11:125644132 G>A

Gene: CHEK1 Transcript: NM_001274.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CHEK1

Transcript

NM_001274.5

Protein

NP_001265.2:p.(Arg322His)

gnomAD AF

2.2306104189334213e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant (NM_001274.5:c.965G>A, p.Arg322His) is a missense substitution in CHEK1, a gene with limited but emerging evidence for germline loss-of-function disease association. No CSPEC or VCEP framework exists for CHEK1; assessment follows generic ACMG/AMP 2015 guidelines.

The variant is observed at extremely low frequency in gnomAD population databases (v2.1 AF=0.004%, v4.1 AF=0.002%), meeting the PM2 criterion at supporting strength.

Multiple in silico predictors unanimously suggest a neutral effect: REVEL score 0.055, BayesDel score -0.267, and SpliceAI max delta 0.03, meeting BP4 at supporting_benign strength.

ClinVar reports this variant as Uncertain significance (VCV2397701, criteria provided, single submitter: Ambry Genetics). There are no reputable sources classifying this variant as pathogenic or benign.

No variant-specific functional studies, de novo observations, segregation data, or case-control enrichment data were identified in the available literature or databases.

The final evidence profile includes one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). These cancel, resulting in a classification of Uncertain significance per the ACMG/AMP 2015 combination 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	This is a missense variant (c.965G>A, p.Arg322His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable per the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No evidence identified of a different nucleotide change at codon 322 producing the same p.Arg322His substitution that has been classified as pathogenic.	clinvar
PS2	Not met	No de novo occurrence data available for this variant. PS2 requires confirmation of de novo origin with confirmed maternity and paternity.
PS3	Not met	No variant-specific or systematically characterized range functional data identified for CHEK1 p.Arg322His. OncoKB reports unknown oncogenic effect with no curated functional studies. The REVEL score of 0.055 and BayesDel score of -0.266 are computational predictions, not experimental functional evidence.	oncokb revel bayesdel
PS4	Not met	No case-control data or statistically significant enrichment data available comparing prevalence of this variant in affected individuals versus general population controls.
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter; Ambry Genetics). PS5 requires a reputable source recently reporting the variant as pathogenic where independent evaluation is not possible.	clinvar
PM1	Not met	Position p.Arg322 lies in the SQ/TQ cluster domain (SCD) of CHEK1, a regulatory region involved in checkpoint signaling. However, this specific residue is not a statistically significant hotspot (cancerhotspots.org negative), and no well-established critical functional domain annotation supports PM1 at this exact residue within the broader SCD region. Domain-level inference from the literature is insufficient without direct evidence that position 322 is functionally critical.	oncokb
PM2	Met	This variant is present at extremely low frequency in gnomAD population databases: v2.1 overall AF=0.004% (10/251,222 alleles, 0 homozygotes) and v4.1 overall AF=0.002% (36/1,613,908 alleles, 0 homozygotes), both well below the 0.1% PM2 threshold. Maximum subpopulation frequency is 0.0275% (South Asian, v4.1). Downgraded to supporting strength given the variant is not completely absent and the limited germline disease association of CHEK1.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (p.Arg322) pathogenic missense comparator variants were identified in ClinVar; automated PM5 candidate harvesting could not confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No de novo occurrence data available for this variant. PM6 requires a de novo observation without confirmed maternity and paternity.
PP1	Not met	No co-segregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	CHEK1 has not been established as a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Insufficient constraint data to support PP2.
PP3	Not met	Multiple lines of computational evidence predict a benign effect: REVEL score 0.055 (well below pathogenic threshold), BayesDel score -0.267 (negative, benign-leaning), and SpliceAI max delta 0.03 (no predicted splice impact). These scores do not support a deleterious effect and therefore do not meet PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available to assess whether the phenotype is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (1-star, single submitter: Ambry Genetics), not Pathogenic. PP5 requires a reputable source reporting the variant as pathogenic; a VUS classification does not satisfy this criterion even at supporting strength.	clinvar
BA1	Not met	Maximum population allele frequency in gnomAD is 0.0275% (South Asian, v4.1), well below the 1% BA1 threshold. This variant is not common enough to be considered a benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	Maximum population allele frequency in gnomAD is 0.0275% (South Asian, v4.1), well below the 0.3% BS1 threshold. This variant is not observed at a frequency greater than expected for the disorder.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual for a fully penetrant disorder with a recessive or dominant inheritance pattern relevant to CHEK1.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a neutral effect for CHEK1 p.Arg322His. Computational predictions (REVEL 0.055, BayesDel -0.267) are in silico tools, not experimental functional evidence meeting BS3 requirements.	revel bayesdel
BS4	Not met	No segregation data available to assess lack of co-segregation with disease in affected family members.
BP1	Not met	Although loss-of-function is supported as a disease mechanism for CHEK1 (based on germline literature review), CHEK1 has not been established as a gene where ONLY truncating variants cause disease. Missense variants are also plausible in the kinase and regulatory domains, and BP1 is not met.	pvs1_gene_context
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion. BP3 applies only to in-frame deletions/insertions in a repetitive region without a known function.
PM3	N/A	No evidence of biallelic inheritance pattern (trans with a pathogenic variant) relevant to CHEK1. PM3 applies to recessive disorders; CHEK1-associated cancer predisposition is primarily assessed under autosomal dominant models.
PM4	N/A	This is a substitution variant, not an in-frame deletion/insertion or stop-loss variant. PM4 applies only to protein length changes due to in-frame indels or stop-loss variants in non-repeat regions.
BP2	Not met	No data available on whether this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4	Met	Multiple lines of computational evidence predict no damaging effect: REVEL score 0.055 (well below the 0.29 benign threshold), BayesDel score -0.267 (negative, indicating benign), and SpliceAI max delta 0.03 (no predicted splice impact). Three independent in silico tools unanimously predict a neutral/benign effect.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case where an alternate molecular basis for disease was identified.
BP6	Not met	ClinVar classification for this variant is Uncertain significance (1-star, single submitter), not Benign or Likely Benign. BP6 requires a reputable source reporting the variant as benign; a VUS classification does not satisfy this criterion.	clinvar
BP7	N/A	This is a missense variant (c.965G>A, p.Arg322His), not a synonymous variant. BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence.

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