Classification rationale

PM2 BP4 VUS

CHEK1 c.1070G>A

This missense variant in CHEK1 (c.1070G>A, p.Ser357Asn) is absent from gnomAD population databases (PM2_Supporting).¹ Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303, and SpliceAI max delta 0.03 indicates no splice impact (BP4_Supporting).² The variant is absent from ClinVar and COSMIC; no experimental functional data, segregation data, or de novo reports were identified.³ One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met; these cancel and no pathogenic or benign combination is reached per the generic ACMG/AMP 2015 classification framework. The variant is classified as a Variant of Uncertain Significance (VUS).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_001274.5 · variants mapped to exon structure

CHEK1 NM_001274.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (genomes/exomes), meeting the PM2 threshold of <0.1% population allele frequency.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (genomes/exomes).Absent from gnomAD-Canada v1.0 (genomes).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple in silico tools predict a benign effect: REVEL score 0.167, BayesDel score -0.303 (negative/benign), and SpliceAI max delta score 0.03 indicates no significant splice impact. Computational evidence supports a benign interpretation.

REVEL: 0.167 (benign-leaning).BayesDel: -0.303 (benign).SpliceAI: max delta 0.03 (no predicted splice impact).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic variant with the same amino acid change (p.Ser357Asn) has been reported in ClinVar.

PS2 No de novo report with confirmed paternity and maternity was identified for this variant.

PS3 No variant-specific functional data identified.

PS4 No case-control studies, odds ratio data, or statistical enrichment evidence available for this variant.

PM1 Residue S357 lies in the C-terminal regulatory domain of CHEK1, outside the well-characterized kinase domain (residues ~1-265).

PM6 No de novo report was identified for this variant.

PP1 No segregation data available for this variant.

PP2 No HCI prior score or gene-specific missense constraint data available for CHEK1.

PP3 Multiple in silico tools predict a benign effect: REVEL score 0.167 (well below pathogenic threshold of 0.5), BayesDel score -0.303 (negative/benign), SpliceAI max delta 0.03 (no predicted splice impact).

PP4 No patient phenotype data provided to assess specificity for CHEK1-related hereditary cancer predisposition.

PP5 Variant is absent from ClinVar; no reputable source has classified this variant.

Benign

BA1 Variant is absent from gnomAD; does not meet the BA1 threshold of >1% allele frequency in any population.

BS1 Variant is absent from gnomAD; does not meet the BS1 threshold of >0.3% allele frequency in population databases.

BS2 Variant is absent from population databases; no evidence of observation in healthy adults to support BS2.

BS3 No functional studies demonstrating a neutral or benign effect for this variant.

BS4 No segregation data showing lack of cosegregation with disease.

BP1 BP1 applies to truncating variants in genes where only truncating variants cause disease.

BP2 No observation of this variant in trans with a known pathogenic CHEK1 variant.

BP5 No case-level data showing an alternate molecular basis for disease in an individual harboring this variant.

BP6 Variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign.

N/A · 3 PVS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.167. BayesDel score = -0.303191.

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. CHEK1, an intracellular kinase, is overexpressed in various solid and hematologic malignancies.

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

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots