NM_007194.4:c.400G>C

CHEK2 · NP_009125.1:p.(Asp134His) · NM_007194.4

GRCh37: chr22:29121275 C>G · GRCh38: chr22:28725287 C>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Asp134His)

gnomAD AF

1.1152637474844607e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007194.4:c.400G>C (p.Asp134His) in CHEK2 is a rare missense variant observed at extremely low frequency in population databases (gnomAD v2.1 AF=0.00212%, 6/282,722 alleles), meeting PM2 (supporting).

Multiple in silico predictors are consistent with a benign effect: REVEL score 0.37, BayesDel score -0.100, and SpliceAI max delta 0.01 (no predicted splicing impact), meeting BP4 (supporting).

No variant-specific functional evidence, case-control data, segregation data, or de novo reports were identified in the literature. The ENIGMA CHEK2gether functional study (PMID:37449874) assessed 430 CHEK2 missense VUS but did not include this variant.

ClinVar reports this variant as Uncertain significance (10 clinical laboratories) with one Likely benign submission. No expert panel classification is available.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as either pathogenic or benign. 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	This is a missense variant (c.400G>C, p.Asp134His). It does not fall into the null-variant classes of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not met	No known pathogenic variant at the same amino acid position (p.Asp134) with a different nucleotide change was identified in ClinVar or the literature. The PM5 candidate search did not find any same-residue comparator variants.	pm5_candidates clinvar
PS2	Not met	No de novo occurrence data for NM_007194.4:c.400G>C was identified in ClinVar, the reviewed literature, or any other source.	clinvar
PS3	Not met	No variant-specific functional evidence supporting a damaging effect was identified. The ENIGMA CHEK2gether functional study (PMID:37449874) assessed 430 CHEK2 missense VUS but did not include NM_007194.4:c.400G>C (p.Asp134His) in its analysis.	PMID:37449874 PMID:30851065 oncokb
PS4	Not met	No case-control enrichment data or case series specific to this variant was identified. While this variant has been observed in clinical testing (ClinVar submissions from multiple laboratories), the absence of controlled case-control data precludes application of PS4.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	No expert panel or reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance (10 submitters) and Likely benign (1 submitter), with review status 'criteria provided, single submitter'.	clinvar
PM1	Not met	The p.Asp134 residue does not lie in a statistically significant mutational hotspot. Hotspot analysis found no enrichment at this position. The CHEK2 VCEP framework does not provide domain-level PM1 specifications.	cspec
PM2	Met	This variant is extremely rare in population databases. In gnomAD v2.1, it is observed at AF=2.12×10⁻⁵ (6/282,722 alleles, 0 homozygotes) and in gnomAD v4.1 at AF=1.12×10⁻⁵ (18/1,613,968 alleles, 0 homozygotes). The highest subpopulation frequency is 4.01×10⁻⁵ in African/African American. These frequencies are well below the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same amino acid residue (p.Asp134) with a different amino acid change was identified. Automated PM5 candidate harvesting did not find any eligible same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PM6	N/A	No de novo occurrence data is available for this variant. PM6 cannot be applied without a confirmed de novo report.	clinvar
PP1	Not met	No co-segregation data is available for this variant. None of the reviewed publications reported segregation analysis for NM_007194.4:c.400G>C.	clinvar
PP2	Not met	CHEK2 is a cancer predisposition gene in which both truncating and missense variants are established disease mechanisms. PP2 is intended for genes where missense variants are a common mechanism of disease and benign missense variation is rare, but the CHEK2 VCEP does not provide a specific PP2 specification, and the gene has a substantial burden of rare missense variants of uncertain significance.	cspec PMID:25741868
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.37 (below the pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). All three independent computational tools agree on a likely benign or neutral effect.	revel bayesdel spliceai
PP4	Not met	No specific phenotype data or clinical presentation details for individuals carrying this variant were identified in the reviewed literature or ClinVar submissions.	clinvar
PP5	N/A	No reputable source or expert panel has classified this variant as pathogenic. None of the evaluated PP5-candidate publications (PMID:15604628, PMID:18163131, PMID:24432435, PMID:26389210, PMID:35802134) were found to classify or mention this specific variant.	clinvar
BA1	Not met	The allele frequency is far below the BA1 threshold of 1%. gnomAD v2.1 AF=0.00212% (6/282,722 alleles) and v4.1 AF=0.00112% (18/1,613,968 alleles).	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency is below the BS1 threshold of 0.3%. gnomAD v2.1 AF=0.00212% (6/282,722 alleles) and v4.1 AF=0.00112% (18/1,613,968 alleles). The highest subpopulation frequency is 0.00401% in African/African American.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous observations in gnomAD (0 homozygotes in both v2.1 and v4.1). No data on asymptomatic adult heterozygote frequency above expected controls.	gnomad_v2 gnomad_v4
BS3	Not met	No variant-specific functional evidence demonstrating a benign effect was identified. The ENIGMA CHEK2gether functional study (PMID:37449874) did not include this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional data.	PMID:37449874 PMID:30851065 oncokb
BS4	Not met	No segregation data is available for this variant. Lack of segregation with disease in affected families cannot be assessed.	clinvar
BP1	N/A	CHEK2 disease mechanism includes both truncating and missense pathogenic variants. BP1 is specifically intended for genes in which only truncating variants cause disease and missense variants are not an established mechanism.	PMID:25741868 cspec
BP2	Not met	No observation of this variant in trans with a known pathogenic CHEK2 variant was identified.	clinvar
BP4	Met	Multiple independent in silico predictors are consistent with a benign or neutral effect. REVEL score is 0.37 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). The concordance of three orthogonal computational tools supports a lack of functional effect.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternative molecular basis for disease was identified in the reviewed data.	clinvar
BP6	Not met	No reputable source has classified this variant as benign. ClinVar reports predominantly Uncertain significance (10 clinical laboratories) with one Likely benign submission (Myriad Genetics). No expert panel classification is available.	clinvar
BP7	N/A	This is a missense variant (c.400G>C, p.Asp134His). BP7 applies only to synonymous variants with no predicted splicing impact.	spliceai
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This is a single nucleotide substitution variant.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CHEK2-related cancer predisposition is autosomal dominant.	cspec
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants that change protein length. This is a missense substitution that does not alter protein length.

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