Starting

Initialising…

CHEK2

Final classification

VUS

CHEK2 c.-6-8T>G · p.?

CHEK2

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.

Gene

CHEK2

Transcript

NM_007194.4

HGVS · transcript:coding

NM_007194.4:c.-6-8T>G

Consequence

N/A

GRCh38

chr22:28734735 A>C

GRCh37

chr22:29130723 A>C

Basis Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting. ▾

Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

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 ↗

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

Benign evidence

—

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= 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.

PMID PMID:25741868

PMID PMID:25741868 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BP4 supports · met →PM2 supports · met

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC