Classification rationale

PM2 BP4 VUS

CHEK2 c.-6-8T>G

The CHEK2 NM_007194.4:c.-6-8T>G (NP_009125.1:p.?) variant has been reported in ClinVar as likely benign by a single clinical laboratory.¹ This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06; highest observed population AF 1.6001e-05), supporting rarity but not a benign frequency threshold.² In silico splicing analysis does not support a meaningful splice effect, with SpliceAI showing a maximum delta score of 0.10.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 · 18 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

This variant is absent from gnomAD v2.1 and is present only 3 times in 1,612,954 alleles in gnomAD v4.1 (overall AF 1.85994e-06, 0.00019%; highest observed population AF 1.6001e-05, 0.00160%), which is well below a 0.1% rarity threshold and supports rarity.

Absent from gnomAD v2.1.Present at extremely low frequency in gnomAD v4.1 with no homozygotes.

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Available computational evidence supports no meaningful splice effect. SpliceAI showed a maximum delta score of 0.10, which is below commonly used thresholds for significant splice disruption and argues against an abnormal splicing effect.

SpliceAI DS_AG 0.05DS_AL 0.10DS_DG 0.00

spliceai ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PS2 No confirmed de novo occurrence data were identified for this variant.

PS3 No well-established functional study was identified showing that this variant damages CHEK2 function or causes abnormal splicing.

PS4 Available evidence does not show an increased prevalence of this variant in affected individuals compared with controls.

PM1 This variant is located in a non-canonical intronic region rather than a known CHEK2 mutational hotspot or well-established critical functional domain with low benign variation.

PM6 No assumed de novo occurrence without parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging effect on splicing.

PP4 No phenotype information was provided that would allow assessment of whether the clinical presentation is highly specific for CHEK2-related disease.

PP5 This criterion was not used because assertion-based evidence without accessible supporting data is not considered sufficient for independent classification.

Benign

BA1 The observed population frequency is far below a stand-alone benign threshold.

BS1 The observed population frequency is too low for benign strong evidence.

BS2 Available population data do not establish this variant as observed in a context that would support BS2 for CHEK2-related disease.

BS3 No well-established functional study was identified showing that this variant has no damaging effect on CHEK2 function or splicing.

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

BP2 No phase data with another pathogenic variant were identified for this variant.

BP5 No alternate molecular explanation for the observed phenotype was provided, so BP5 could not be assessed.

BP6 This criterion was not used because assertion-based benign evidence without accessible supporting data is not considered sufficient for independent classification.

BP7 Although SpliceAI does not predict a significant splice effect, BP7 was not applied because the reviewed evidence does not provide the additional contextual support typically used for this criterion in a noncoding intronic variant.

N/A · 8 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85994e-06; MAF= 0.00019%, 3/1612954 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6001e-05; MAF= 0.00160%, 1/62496 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,612,954
0 hom

Remaining individuals 1 / 62,496	0.0016%
African/African American 1 / 75,026	0.0013%
European (non-Finnish) 1 / 1,179,672	8.5e-05%

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

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Standards and guidelines for the interpretation of sequence variants: a joint co

PMID 25741868 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PM2 supporting

→BP4 supporting

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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