Classification rationale

PM2 BP4 VUS

CHEK2 c.731A>G

The CHEK2 c.731A>G (p.Lys244Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 7 clinical laboratories.¹ The variant is present at very low frequency in gnomAD, with AF 1.06e-05 in v2.1 and 9.29e-06 in v4.1, and no homozygotes were observed, which supports rarity.² In silico data argue against a deleterious effect, with REVEL 0.062 and SpliceAI predicting no significant splice impact (max delta score 0.00).³

PM2 + BP4 → VUS

1 cosmicclinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗prefetch

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

CHEK2 NM_007194.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 9.29408e-06; MAF= 0.00093%, 15/1613930 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000106761; MAF= 0.01068%, 8/74934 alleles, homozygotes = 0); grpmax FAF= 7.712e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.06089e-05; MAF= 0.00106%, 3/282782 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00513e-05; MAF= 0.00401%, 1/24968 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00093% · 15 / 1,613,930
0 hom · FAF 0.0077%

African/African American 8 / 74,934	0.011%
Admixed American 1 / 60,002	0.0017%
European (non-Finnish) 6 / 1,179,972	0.00051%

+ 7 not observed (Remaining individuals, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, Amish)

gnomAD v2.1

0.0011% · 3 / 282,782
0 hom · FAF 0.00029%

African/African American 1 / 24,968	0.004%
European (non-Finnish) 2 / 129,138	0.0015%

+ 6 not observed (Admixed 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 (7 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.

Hotspots ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots