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

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 · 2 applied · 19 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

The variant is present at very low frequency in population databases (gnomAD v2.1 AF 1.06e-05, 3/282782; gnomAD v4.1 AF 9.29e-06, 15/1613930) with no homozygotes observed, supporting rarity.

gnomAD v2.1 total AF 1.0608878924401129e-05gnomAD v4.1 total AF 9.294083386516143e-060 homozygotes in both datasets

BP4 supporting review Benign

Computational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00.

REVEL 0.062SpliceAI DS max 0.00

Assessed · not applied · 4 not met · 15 not assessed

Pathogenic

PS1 No evidence was retrieved showing another nucleotide change that produces the same amino acid substitution and is established as pathogenic/likely pathogenic.

PS2 No confirmed de novo data were retrieved.

PS3 Functional publications were cited in ClinVar/literature triage, but no validated assay result for CHEK2 p.(Lys244Arg) was extracted with sufficient detail to support damaging functional evidence.

PS4 The variant has been reported in ClinVar, but case-control enrichment or a case count meeting ACMG/AMP evidence thresholds was not retrieved.

PM1 Cancer Hotspots did not identify residue K244 as a statistically significant hotspot, and no mutational hotspot or well-established critical functional residue evidence was retrieved.

PM5 No evidence was retrieved showing a different pathogenic missense change at codon 244.

PM6 No assumed de novo observations were retrieved.

PP1 No segregation data were retrieved.

PP2 No gene-level missense constraint or pathogenic missense enrichment evidence specific enough to support PP2 was retrieved.

PP3 Available computational evidence does not support a deleterious effect: REVEL is low (0.062) and SpliceAI predicts no significant splice impact (max delta 0.00).

PP4 No phenotype or family history data were provided to support a highly specific CHEK2-related presentation.

Benign

BA1 Population frequency is far below stand-alone benign thresholds.

BS1 Population frequency is too low to support a benign frequency-based criterion.

BS2 No evidence was retrieved showing the variant in healthy adults at a frequency or context sufficient for BS2.

BS3 No well-established functional study demonstrating normal CHEK2 protein function for p.(Lys244Arg) was extracted.

BS4 No segregation data showing lack of cosegregation were retrieved.

BP1 No gene-specific evidence was retrieved to support that truncating variants predominate and that missense variation is generally not disease-causing in CHEK2.

BP2 No allelic phase or co-occurrence data were retrieved.

BP5 No alternate molecular explanation for the phenotype was retrieved.

N/A · 7 PVS1 · PM3 · PM4 · PP5 · BP3 · BP6 · BP7

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

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