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CHEK2c.1597A>TUncertain significance
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Variant interpretation report

CHEK2 c.1597A>T, p.(Thr533Ser)

NM_007194.4:c.1597A>T NP_009125.1:p.(Thr533Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CHEK2

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is ClinGen CHEK2 VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen CHEK2 VCEP v1.0.0, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 19 not met · 2 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel −0.503, and SpliceAI max delta 0.00 (BP4_Supporting).

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.

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).

Met · 2

PM2 SupportingThis 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0/N total alleles)
  • absent from gnomAD v4.1
  • absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.054
  • BayesDel −0.503
  • SpliceAI 0.00. All predictors consistently indicate no damaging effect.
Sources
revelbayesdelspliceai ↗

Not met · 19 · evaluated, threshold not reached

PS1 No prior evidence of a different pathogenic nucleotide change at position c.1597 in CHEK2. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at the same nucleotide position identified in ClinVar
  • literature
  • or VCEP materials.
Still missing
  • A pathogenic comparator at c.1597 would be required to meet PS1.
PS2 No de novo observation for this variant has been reported in any available source. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar submissions
  • literature
  • or VCEP materials.
Still missing
  • De novo confirmation with parental testing would be required to meet PS2.
PS3 No well-established functional studies demonstrate a damaging effect. In silico predictors (REVEL 0.054, BayesDel −0.503) are consistent with a benign impact. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.054 (benign range)
  • BayesDel score −0.503 (benign range)
  • OncoKB classification 'Unknown Oncogenic Effect' with no variant-specific functional data.
Still missing
  • Well-established functional studies (e.g.
  • kinase assay
  • cell-based DNA damage response) for this specific variant would be required to meet PS3.
Sources
revelbayesdeloncokb ↗
PS4 No case-control data are available. The variant is absent from gnomAD, preventing statistical comparison. Two ClinVar submissions classify as VUS without providing case counts. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS from 2 clinical laboratories
  • no case-control or odds ratio data.
Still missing
  • Case-control data or significantly enriched prevalence in affected individuals would be required to meet PS4.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 The variant (p.Thr533Ser) lies in the C-terminal region of CHEK2, outside the kinase domain (residues ~220–486). No statistically significant hotspot was identified, and the residue is not in a critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis negative
  • residue 533 is C-terminal to the kinase domain
  • VCEP materials contain no domain-level PM1 rules.
Sources
cspec ↗
PM6 No de novo observation reported in any available source. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar submissions or literature.
Still missing
  • Confirmed de novo status with parental testing would be required to meet PM6.
PP1 No co-segregation data in affected families have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No co-segregation data in any ClinVar submission or publication.
Still missing
  • Co-segregation analysis in affected families would be required to meet PP1.
PP3 Multiple in silico predictors are consistent with a benign effect. REVEL score 0.054 (well below typical pathogenic threshold of ~0.5), BayesDel score −0.503 (well below pathogenic threshold of ~0.07), and SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL 0.054 (benign)
  • BayesDel −0.503 (benign)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No specific phenotype data are available for individuals carrying this variant. ClinVar submissions list non-specific 'Hereditary cancer-predisposing syndrome' without detailed clinical information. Details ▾Hide ▴
Evidence considered
  • ClinVar submissions with non-specific condition labels
  • no detailed phenotype data available.
Still missing
  • Detailed clinical phenotypes for variant carriers would strengthen PP4 assessment.
Sources
clinvar ↗
PP5 The ClinVar classification for this variant is Uncertain Significance (2 submitters), not Pathogenic. No expert panel has classified this variant. No reputable source recently reported it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is VUS
  • no expert panel or reputable source has classified as pathogenic.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, not exceeding the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Minor allele frequency 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from gnomAD. Allele frequency is 0%, not exceeding the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Minor allele frequency 0% in all gnomAD datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observation of this variant in healthy adults reported. The variant is absent from population databases, precluding demonstration of occurrence in healthy controls. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD
  • no healthy adult carriers identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrate no damaging effect. In silico predictions (REVEL 0.054, BayesDel −0.503) are suggestive of benign impact but are not a substitute for experimental functional evidence required for BS3. Details ▾Hide ▴
Evidence considered
  • In silico scores consistent with benign impact
  • but no experimental functional studies available.
Still missing
  • Well-established in vitro or in vivo functional studies showing no deleterious effect on CHEK2 function would be required to meet BS3.
Sources
revelbayesdeloncokb ↗
BS4 No co-segregation data are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Family segregation data showing lack of co-segregation would be required to meet BS4.
BP1 CHEK2 is not a gene for which primarily truncating variants are known to cause disease; both missense and truncating pathogenic variants are established. Details ▾Hide ▴
Evidence considered
  • CHEK2 pathogenic variant spectrum includes both missense and truncating variants.
BP2 Not observed in trans with a pathogenic variant in CHEK2. CHEK2-related cancer predisposition follows autosomal dominant inheritance. Details ▾Hide ▴
Evidence considered
  • No observation in trans with a pathogenic CHEK2 variant.
BP5 No observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No case identified with alternate molecular explanation for phenotype.
BP6 No reputable source has reported this variant as benign. ClinVar classification is Uncertain Significance. Details ▾Hide ▴
Evidence considered
  • ClinVar classification is VUS
  • no benign classification from a reputable source.
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PP2 HCI prior data are unavailable for CHEK2, preventing assessment of whether the gene has a low rate of benign missense variation. PP2 cannot be evaluated without a missense constraint metric. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for CHEK2
  • coding variant c.1597A>T not in HCI database.
Still missing
  • HCI prior (or equivalent missense constraint score) for CHEK2 would be needed to adjudicate PP2.
PS5 PS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868) nor is it defined in the CHEK2 VCEP specifications (version 1.0.0, criteria.json is empty). Unable to adjudicate an undefined criterion. Details ▾Hide ▴
Evidence considered
  • No PS5 definition found in ACMG/AMP 2015 or CHEK2 VCEP v1.0.0.
Still missing
  • PS5 definition not available in the governing framework.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007194.4:c.1597A>T is a missense variant (p.Thr533Ser) and does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework (PMC6185798) does not apply. Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 15
  • not a null variant by ClinGen SVI PVS1 criteria.
Sources
pvs1_variant_assessment
PM5 N/ANo pathogenic missense variant at the same amino acid residue (Thr533) was identified. Automated PM5 candidate harvesting was unable to confirm classic same-residue comparator semantics. Details ▾Hide ▴
Evidence considered
  • Zero same-residue pathogenic comparator candidates identified in ClinVar.
Sources
pm5_candidates
BP7 N/ABP7 is applicable only to synonymous (silent) variants. NM_007194.4:c.1597A>T is a missense variant (p.Thr533Ser). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
CHEK2
Transcript
NM_007194.4
Coding (HGVS c.)
NM_007194.4:c.1597A>T
Protein (HGVS p.)
NP_009125.1:p.(Thr533Ser)
GRCh38
chr22:28687932 T>A
GRCh37
chr22:29083920 T>A
ClinVar
628755

Gene diagram

Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.4. Select a row to find it on the plot.

CHEK2NM_007194.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.010

Other predictors

REVEL
0.054
BayesDel
-0.503

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.054
  • BayesDel −0.503
  • SpliceAI 0.00. All predictors consistently indicate no damaging effect.
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors are consistent with a benign effect. REVEL score 0.054 (well below typical pathogenic threshold of ~0.5), BayesDel score −0.503 (well below pathogenic threshold of ~0.07), and SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
  • REVEL 0.054 (benign)
  • BayesDel −0.503 (benign)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 is applicable only to synonymous (silent) variants. NM_007194.4:c.1597A>T is a missense variant (p.Thr533Ser). Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.054. BayesDel score = -0.502765.

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Richards S et al. · 2015
    This is the ACMG/AMP standards and guidelines for sequence variant interpretation. It defines the criteria framework but does not report data for any specific CHEK2 variant.
    Does not name this variant
    PMID 25741868 ↗
  • 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.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Discusses general criteria for genetic counseling referral but does not report data on specific CHEK2 variants.
    Does not name this variant
    PMID 25394175 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ cancer genetics summary on breast and gynecologic cancers. Discusses CHEK2 at gene level as a cancer predisposition gene but does not report data on NM_007194.4:c.1597A>T.
    Does not name this variant
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ summary on cancer genetics risk assessment and counseling. A general reference document that does not report data on specific CHEK2 variants.
    Does not name this variant
    PMID 26389258 ↗
  • Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline.
    Eggener SE et al. · 2020
    ASCO guideline on tissue-based molecular biomarkers in localized prostate cancer (Oncotype Dx, Prolaris, Decipher). Does not report data on CHEK2 germline variants.
    Does not name this variant
    PMID 31829902 ↗
  • 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.
    Chiu PKF et al. · 2022
    Consensus statements on genetic testing in prostate cancer from Hong Kong professional societies. Discusses CHEK2 as a prostate cancer predisposition gene but does not report data for NM_007194.4:c.1597A>T.
    Does not name this variant
    PMID 35924163 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.