NM_007194.4:c.1597A>T (p.Thr533Ser) is a missense variant in CHEK2 exon 15, absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).1 Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel −0.503, and SpliceAI max delta 0.00 (BP4_Supporting).2 The variant is classified as Uncertain Significance in ClinVar by two clinical laboratories; no expert panel classification is available. No variant-specific functional studies or case-control data have been reported. No publication reviewed mentions NM_007194.4:c.1597A>T.3 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant above VUS under the generic ACMG/AMP 2015 combination rules (PMID:25741868).4
CHEK2
Final classification
VUS
CHEK2 c.1597A>T · p.Thr533Ser
CHEK2
NM_007194.4:c.1597A>T (p.Thr533Ser) is a missense variant in CHEK2 exon 15, absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CHEK2 c.1597A>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
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, v4.1, and gnomAD-Canada v1.0, supporting pathogenicity at the PM2 supporting level (population frequency <0.1%).
Absent from gnomAD v2.1 (0/N total alleles)absent from gnomAD v4.1absent from gnomAD-Canada v1.0.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score 0.054 (benign), BayesDel score −0.503 (benign), and SpliceAI max delta 0.00 (no predicted splice alteration).
REVEL 0.054BayesDel −0.503SpliceAI 0.00. All predictors consistently indicate no damaging effect.
Assessed · not applied
Pathogenic
PS1
No prior evidence of a different pathogenic nucleotide change at position c.1597 in CHEK2.
PS2
No de novo observation for this variant has been reported in any available source.
PS3
No well-established functional studies demonstrate a damaging effect.
PS4
No case-control data are available.
PM1
The variant (p.Thr533Ser) lies in the C-terminal region of CHEK2, outside the kinase domain (residues ~220–486).
PM6
No de novo observation reported in any available source.
PP1
No co-segregation data in affected families have been reported for this variant.
PP2
HCI prior data are unavailable for CHEK2, preventing assessment of whether the gene has a low rate of benign missense variation.
PP3
Multiple in silico predictors are consistent with a benign effect.
PP4
No specific phenotype data are available for individuals carrying this variant.
PP5
The ClinVar classification for this variant is Uncertain Significance (2 submitters), not Pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from gnomAD.
BS2
No observation of this variant in healthy adults reported.
BS3
No well-established functional studies demonstrate no damaging effect.
BS4
No co-segregation data are available to evaluate lack of segregation with disease.
BP1
CHEK2 is not a gene for which primarily truncating variants are known to cause disease; both missense and truncating pathogenic variants are established.
BP2
Not observed in trans with a pathogenic variant in CHEK2.
BP5
No observation of this variant in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 628755)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.054. BayesDel score = -0.502765.
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. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.
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.
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
35924163 ↗
Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology.
CLINVAR