NM_007194.4:c.906A>C

CHEK2 · NP_009125.1:p.(Glu302Asp) · NM_007194.4

GRCh37: chr22:29099495 T>G · GRCh38: chr22:28703507 T>G

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Glu302Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CHEK2 c.906A>C (p.Glu302Asp, p.E302D) variant has not been observed in COSMIC and has been reported in ClinVar as a variant of uncertain significance.

This variant is present at low frequency in population databases, with gnomAD v2.1 total allele frequency 0.00342% (8/234112) and gnomAD v4.1 total allele frequency 0.00097% (14/1437854); the highest observed subpopulation frequency is 0.03471% (2/5762) in Middle Eastern individuals, which remains below a 0.1% rarity threshold.

In silico data do not show a consistent damaging signal: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, REVEL is 0.41, and BayesDel is 0.0235302.

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 substitution, p.(Glu302Asp), and it does not fall in a nonsense, frameshift, or canonical +/-1,2 splice category for which PVS1 is typically considered.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No alternate nucleotide change producing the same p.(Glu302Asp) amino acid substitution with an established pathogenic classification was identified in ClinVar, so PS1 is not met.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar
PS3	Not assessed	Published CHEK2 functional studies were identified in the literature set, but an exact validated abnormal functional result for p.(Glu302Asp) was not confirmed from the available evidence, so PS3 is not applied.	PMID:30851065 PMID:37449874 PMID:37725924
PS4	Not assessed	This variant has been reported in ClinVar, but no variant-specific case-control enrichment data or exact odds ratio demonstrating increased prevalence in affected individuals were identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not show that residue 302 lies in a statistically significant hotspot or a well-established critical region without benign variation, so PM1 is not met.	hotspots
PM2	Met	This variant is rare in population databases. In gnomAD v2.1 the total allele frequency is 0.00342% (8/234112), and in gnomAD v4.1 the total allele frequency is 0.00097% (14/1437854) with highest observed subpopulation frequency 0.03471% (2/5762) in Middle Eastern individuals; these values are below the 0.1% rarity threshold, supporting PM2 at a supporting level.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is a recessive trans-with-pathogenic criterion, whereas the retrieved CHEK2 disease context is autosomal dominant cancer predisposition.	cspec
PM4	N/A	This variant is a missense substitution and does not change protein length, so PM4 is not applicable.	pvs1_variant_assessment
PM5	Not met	Other codon 302 missense changes were identified in ClinVar, but they are reported as uncertain significance or conflicting rather than established pathogenic variants, so PM5 is not met.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence shows that missense variants can be relevant in CHEK2, but the retrieved evidence does not establish a gene-level missense mechanism or missense constraint basis sufficient to apply PP2 for this variant.	PMID:37449874 cspec
PP3	Not met	Available computational evidence does not support a damaging prediction. SpliceAI shows no significant predicted splice effect with a maximum delta score of 0.01, REVEL is 0.41, and BayesDel is 0.0235302; taken together, these results do not reach a consistent damaging threshold for PP3.	spliceai revel bayesdel
PP4	Not assessed	No phenotype information specific enough to support a highly CHEK2-specific clinical presentation was provided.	cspec
PP5	N/A	PP5 was not used because a reputable-source assertion alone is not sufficient evidence for classification here.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. The highest observed frequency is 0.03471% in gnomAD v4.1 Middle Eastern individuals, which is well below 1%.	gnomad_v4
BS1	Not met	Population frequency is below the benign strong threshold. The highest observed frequency is 0.03471% in gnomAD v4.1, which is below the 0.3% threshold, so BS1 is not met.	gnomad_v4
BS2	Not met	One homozygote is present in gnomAD v4.1, but no phenotype data are available for that individual, and this alone is not sufficient to establish observation in healthy adults for CHEK2-related cancer predisposition.	gnomad_v4 cspec
BS3	Not assessed	Published CHEK2 functional studies were identified, but an exact validated normal functional result for p.(Glu302Asp) was not confirmed from the available evidence, so BS3 is not applied.	PMID:30851065 PMID:37449874 PMID:37725924
BS4	Not assessed	No non-segregation data were identified for this variant.	clinvar
BP1	Not met	Although loss of function is an established CHEK2 disease mechanism, missense variants have also been functionally implicated in CHEK2, so a missense change alone does not support BP1.	pvs1_gene_context PMID:37449874
BP2	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant condition, or in cis with a pathogenic variant.	clinvar
BP3	Not assessed	No evidence was identified that this variant lies in a repetitive region or a region without known function that would support BP3.	hotspots
BP4	Not met	Available computational evidence does not provide a consistent benign prediction. SpliceAI predicts no significant splice effect, but REVEL is 0.41 and BayesDel is 0.0235302, which together do not support BP4.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or clearly independent cause for disease was identified.	clinvar
BP6	N/A	BP6 was not used because a reputable-source assertion alone is not sufficient evidence for classification here.	clinvar
BP7	N/A	BP7 is a synonymous or noncoding splice-neutral criterion, and this variant is a missense substitution.	spliceai

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