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CHEK1c.922A>TUncertain significance
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Variant interpretation report

CHEK1 c.922A>T, p.(Ser308Cys)

NM_001274.5:c.922A>T NP_001265.2:p.(Ser308Cys) 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 CHEK1

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 Not recorded. 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

NM_001274.5:c.922A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population (allele frequency well below 0.1% threshold).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple in silico predictors consistently predict no deleterious effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00, supporting a benign interpretation.

Recorded classification: Uncertain significance

gene-specific framework 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
Not recorded

A ClinVar laboratory submission summary was not recorded.

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

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 Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 15 not met · 9 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001274.5:c.922A>T (p.Ser308Cys) is a missense variant in CHEK1 that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

Multiple in silico predictors (REVEL 0.059, BayesDel -0.329, SpliceAI max delta 0.00) consistently predict no deleterious effect, meeting BP4 at supporting benign strength.

The variant is absent from ClinVar with no prior classifications, and no variant-specific functional or clinical publications were identified.

The PVS1 null-variant framework does not apply to this missense substitution; no truncation, frameshift, or canonical splice disruption is predicted.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, resulting in a variant of uncertain significance (VUS) per generic ACMG/AMP 2015 combination rules.

Met · 2

PM2 SupportingNM_001274.5:c.922A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population (allele frequency well below 0.1% threshold). Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada v1.0: AC=0
  • AN=0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple in silico predictors consistently predict no deleterious effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.059 (benign-leaning)
  • BayesDel: -0.329 (benign-leaning)
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 15 · evaluated, threshold not reached

PVS1 NM_001274.5:c.922A>T is a missense variant (p.Ser308Cys) that does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per PMC6185798. Details ▾Hide ▴
Evidence considered
  • Missense substitution at codon 308
  • variant bucket 'other'
  • generic PVS1 framework not applicable.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 No alternate nucleotide change at c.922 resulting in the same amino acid (p.Ser308Cys) has been established as pathogenic; the variant is absent from ClinVar and no comparator variants were identified. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no same-residue pathogenic comparators identified.
Sources
clinvar ↗pm5_candidates
PS3 No variant-specific functional studies were identified in the literature; OncoKB reports unknown oncogenic effect and the variant is absent from COSMIC. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • COSMIC: no entries
  • literature: no publications found.
Still missing
  • No functional data available for p.Ser308Cys.
Sources
oncokb ↗
PM1 p.Ser308Cys does not lie in a statistically significant mutational hotspot per cancerhotspots.org and no domain-level functional characterization specific to this residue in CHEK1 was identified. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not significant
  • no critical functional domain literature for this residue identified.
PM5 No pathogenic missense variant at codon 308 with a different amino acid change was identified in ClinVar; zero same-residue comparator candidates were found. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue pathogenic comparators at codon 308.
Sources
pm5_candidatesclinvar ↗
PP2 HCI prior probability of pathogenicity data are not available for CHEK1; cannot establish that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • HCI Prior: gene not supported
  • insufficient data to satisfy PP2 requirements.
Still missing
  • Gene-specific missense constraint metrics (e.g.
  • HCI prior) for CHEK1.
PP3 Multiple in silico predictors uniformly suggest a benign effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00. These scores do not support a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.059 (benign-leaning)
  • BayesDel: -0.329 (benign-leaning)
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP5 The variant is absent from ClinVar; no reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: variation ID not found
  • no submitters
  • no classifications.
Sources
clinvar ↗
BA1 The variant is absent from all gnomAD datasets (v2.1, v4.1, Canada); allele frequency is 0%, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada: AC=0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all gnomAD datasets; allele frequency is 0%, below the 0.3% BS1 threshold for a benign allele frequency observation. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: absent
  • gnomAD-Canada: AC=0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 No well-established functional studies demonstrating no deleterious effect of p.Ser308Cys were identified in the literature. Details ▾Hide ▴
Evidence considered
  • No functional studies identified for this variant.
Still missing
  • Functional assay data for p.Ser308Cys demonstrating normal protein function.
BP1 Although CHEK1 loss of function is a supported germline disease mechanism, insufficient evidence exists to establish that truncating variants are the sole or predominant cause of disease while missense variants are not pathogenic. Details ▾Hide ▴
Evidence considered
  • CHEK1 LoF mechanism supported (PMC6185798-compatible)
  • but gene-level data do not clearly establish that missense variants are benign.
Still missing
  • Gene-specific evidence that missense variants are not a common disease mechanism for CHEK1.
Sources
pvs1_gene_context
BP6 The variant is absent from ClinVar; no reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no variation ID
  • no submitters
  • no benign classifications.
Sources
clinvar ↗
BP7 NM_001274.5:c.922A>T is a missense variant (p.Ser308Cys), not synonymous; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • SpliceAI max delta 0.00 confirms no cryptic splice effect.
Sources
spliceai ↗
PS5 No reputable source has recently reported this variant as pathogenic with evidence not available for independent evaluation. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no external classification available.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 De novo status cannot be evaluated; no proband or parental genotype data are available. Details ▾Hide ▴
Still missing
  • Proband and parental genotype data required to assess de novo occurrence.
PS4 No case-control or cohort prevalence data are available to evaluate enrichment in affected individuals. Details ▾Hide ▴
Still missing
  • Case-control or cohort data comparing variant prevalence in affected vs. unaffected individuals.
PM6 Assumed de novo status cannot be evaluated; no proband or parental genotype data are available. Details ▾Hide ▴
Still missing
  • Proband and parental genotype data without confirmed maternity/paternity.
PP1 No family segregation data are available to evaluate co-segregation with disease. Details ▾Hide ▴
Still missing
  • Multi-generational family segregation data.
PP4 No patient phenotype or family history data are available to evaluate specificity for a disease with single genetic etiology. Details ▾Hide ▴
Still missing
  • Detailed patient phenotype and family history information.
BS2 No data are available regarding observation in healthy adults for a disorder expected to have full penetrance at an early age. Details ▾Hide ▴
Still missing
  • Observation data in healthy adult controls with full penetrance expected.
BS4 No family segregation data are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
  • Family segregation data showing lack of co-segregation with disease.
BP2 No data on observation in trans with a pathogenic dominant variant are available. Details ▾Hide ▴
Still missing
  • Genotype data for a dominant pathogenic variant in trans.
BP5 No data are available regarding an alternate molecular basis for disease in this case. Details ▾Hide ▴
Still missing
  • Identification of an alternate molecular cause for the observed phenotype.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ANo proband data available; requires observation in trans with a pathogenic variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AVariant is a missense substitution; PM4 applies only to protein length-changing variants (stop-loss, in-frame indels). Details ▾Hide ▴

No further detail was recorded.

BP3 N/AVariant is a missense substitution; BP3 applies only to in-frame insertions/deletions in repetitive regions. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CHEK1
Transcript
NM_001274.5
Coding (HGVS c.)
NM_001274.5:c.922A>T
Protein (HGVS p.)
NP_001265.2:p.(Ser308Cys)
GRCh38
chr11:125643899 A>T
GRCh37
chr11:125513794 A>T

Gene diagram

Every interpreted variant in CHEK1, mapped onto the exon structure of NM_001274.5. Select a row to find it on the plot.

CHEK1NM_001274.5
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
-0.030
Pangolin splice gain
0.020

Other predictors

REVEL
0.059
BayesDel
-0.329

How the predictions were used

BP4 SupportingMultiple in silico predictors consistently predict no deleterious effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00, supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.059 (benign-leaning)
  • BayesDel: -0.329 (benign-leaning)
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico predictors uniformly suggest a benign effect: REVEL score 0.059, BayesDel score -0.329, and SpliceAI max delta score 0.00. These scores do not support a deleterious prediction. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.059 (benign-leaning)
  • BayesDel: -0.329 (benign-leaning)
  • SpliceAI: max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 NM_001274.5:c.922A>T is a missense variant (p.Ser308Cys), not synonymous; BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • SpliceAI max delta 0.00 confirms no cryptic splice effect.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.059. BayesDel score = -0.329077.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 Captured ClinVar source record 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 ↗

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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.059. BayesDel score = -0.329077.

Functional

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.

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.