Classification rationale

PM2 VUS

CHEK2 c.906A>C

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.¹ 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.² 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 0.0235302.³

PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_007194.4 · variants mapped to exon structure

CHEK2 NM_007194.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

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 v2.1 total AF 3.417e-05gnomAD v4.1 total AF 9.737e-06Highest subpopulation AF 3.471e-04

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 9 not met · 12 not assessed

Pathogenic

PS1 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.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 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.

PS4 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.

PM1 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.

PM5 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.

PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 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.

PP3 Available computational evidence does not support a damaging prediction.

PP4 No phenotype information specific enough to support a highly CHEK2-specific clinical presentation was provided.

Benign

BA1 Population frequency does not meet the benign stand-alone threshold.

BS1 Population frequency is below the benign strong threshold.

BS2 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.

BS3 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.

BS4 No non-segregation data were identified for this variant.

BP1 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.

BP2 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.

BP3 No evidence was identified that this variant lies in a repetitive region or a region without known function that would support BP3.

BP4 Available computational evidence does not provide a consistent benign prediction.

BP5 No alternate molecular diagnosis or clearly independent cause for disease was identified.

N/A · 6 PVS1 · PM3 · PM4 · PP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.73673e-06; MAF= 0.00097%, 14/1437854 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000347102; MAF= 0.03471%, 2/5762 alleles, homozygotes = 1); grpmax FAF= 6.098e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.41717e-05; MAF= 0.00342%, 8/234112 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.68494e-05; MAF= 0.00668%, 2/29918 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00097% · 14 / 1,437,854
1 hom · FAF 0.0061%

Middle Eastern 2 / 5,762	0.035% 1 hom
Admixed American 2 / 54,660	0.0037%
Remaining individuals 1 / 56,382	0.0018%
European (non-Finnish) 9 / 1,031,364	0.00087%

+ 6 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0034% · 8 / 234,112
0 hom · FAF 0.0022%

Admixed American 2 / 29,918	0.0067%
European (non-Finnish) 6 / 101,258	0.0059%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.41. BayesDel score = 0.0235302.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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