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

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

CHEK2 NM_007194.4

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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