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KEAP1c.542_543insTUncertain significance
Print report
Variant interpretation report

KEAP1 c.542_543insT, p.(Ser182GlnfsTer11)

NM_012289.4:c.542_543insT NP_036421.2:p.(Ser182GlnfsTer11) 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 KEAP1

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6, predicted to cause premature termination at codon 192 (NP_036421.2:p.(Ser182GlnfsTer11)), well upstream of the last exon and expected to trigger nonsense-mediated decay. KEAP1 loss of function is an established disease mechanism supported by germline literature (PMID:39373520 identifies pathogenic germline KEAP1 mutations including p.V411fs causing familial multinodular goiter). Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift null variant meets PVS1 at very strong strength.

PM2Supporting
PM2 · supporting

NM_012289.4:c.542_543insT is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold of allele frequency <0.1% in population databases. Complete absence from large, diverse population cohorts supports pathogenicity.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, 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.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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 · 4 not assessed · 8 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

PVS1 (very strong) is met: NM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6 creating a premature termination codon at position 192 (NP_036421.2:p.(Ser182GlnfsTer11)), predicted to trigger nonsense-mediated decay. KEAP1 loss of function is an established germline disease mechanism, supported by published pathogenic frameshift variants causing familial multinodular goiter (PMID:39373520).

PM2 (supporting) is met: the variant is completely absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.

No additional pathogenic criteria are met. The variant has not been reported in affected individuals (PS4 not met), no functional studies are available for this exact variant (PS3 not assessed), no de novo observations exist (PS2/PM6 not met), and no segregation or case-level data is available (PP1/PP4 not met).

No benign criteria are met. The variant is absent from population databases (BA1/BS1 not met), and no functional or clinical evidence supports a benign interpretation.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), PVS1 (very strong) + PM2 (supporting) does not reach a Likely Pathogenic or Pathogenic threshold. The minimum requirement for Likely Pathogenic with PVS1 is one additional moderate criterion, which is not met. The classification is therefore Variant of Uncertain Significance (VUS).

Met · 2

PVS1 Very strongNM_012289.4:c.542_543insT is a frameshift insertion in exon 2 of 6, predicted to cause premature termination at codon 192 (NP_036421.2:p.(Ser182GlnfsTer11)), well upstream of the last exon and expected to trigger nonsense-mediated decay. KEAP1 loss of function is an established disease mechanism supported by germline literature (PMID:39373520 identifies pathogenic germline KEAP1 mutations including p.V411fs causing familial multinodular goiter). Under ClinGen SVI PVS1 recommendations (PMC6185798), this frameshift null variant meets PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
  • Frameshift insertion (c.542_543insT) creating premature termination codon at position 192 of 625 amino acids
  • NMD predicted (PTC in exon 2 of 6
  • well upstream of the last exon-exon junction)
  • KEAP1 germline loss-of-function mechanism supported by published pathogenic frameshift variants (PMID:39373520: p.V411fs in familial multinodular goiter)
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment39373520
PM2 SupportingNM_012289.4:c.542_543insT is absent from gnomAD v2.1 and v4.1, meeting the PM2 threshold of allele frequency <0.1% in population databases. Complete absence from large, diverse population cohorts supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles observed)
  • Absent from gnomAD v4.1 (0 alleles observed)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 15 · evaluated, threshold not reached

PS2 No de novo observation with confirmed maternity and paternity has been reported for NM_012289.4:c.542_543insT in the literature or ClinVar. Details ▾Hide ▴
Still missing
  • No de novo case reports or trio sequencing data available for this variant
PS4 The variant has not been reported in affected individuals. No case reports, cohort studies, or ClinVar submissions document NM_012289.4:c.542_543insT in patients with a KEAP1-associated phenotype. Details ▾Hide ▴
Still missing
  • No case reports or cohort studies reporting this variant in affected individuals
  • No phenotype data available
PM1 The variant does not lie within a statistically significant mutational hotspot as determined by Cancer Hotspots analysis. No ClinGen- or VCEP-defined critical functional domain applies to KEAP1 under the generic ACMG framework, and no domain-level PM1 assignment was identified. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue Ser182 is not in a statistically significant hotspot
PM6 No presumed de novo occurrence (without confirmed maternity and paternity) has been reported for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports available
PP1 No cosegregation data with disease in multiple affected family members is available. KEAP1 is not a well-characterized Mendelian gene with documented family-based linkage studies for this variant. Details ▾Hide ▴
Still missing
  • No family cosegregation studies available
PP4 No affected individuals with this variant and specific phenotype data have been reported. The variant's phenotype specificity cannot be assessed. Details ▾Hide ▴
Still missing
  • No phenotype data available for patients harboring this variant
PP5 No reputable clinical laboratory or diagnostic source has reported NM_012289.4:c.542_543insT as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Still missing
  • No clinical laboratory assertions available
BA1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). BA1 requires an allele frequency >1% in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0% in both v2.1 and v4.1
  • well below the BA1 threshold of >1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). BS1 requires an allele frequency >0.3% in population databases. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0% in both v2.1 and v4.1
  • well below the BS1 threshold of >0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 The variant has not been observed in healthy adult individuals. Its complete absence from gnomAD means no observation in presumed healthy population controls has been documented. Details ▾Hide ▴
Still missing
  • No data on variant presence in healthy adults
BS4 No evidence of non-segregation with disease in affected family members. No family studies are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No observation of this variant in cis with a known pathogenic KEAP1 variant has been reported. No phase information is available from public databases or literature. Details ▾Hide ▴
Still missing
  • No cis/trans phase data available
BP5 No case has been reported where an alternative molecular basis for disease was identified in an individual harboring this variant. No clinical case data is available. Details ▾Hide ▴
Still missing
  • No case data for alternative molecular basis evaluation
BP6 No reputable source has reported NM_012289.4:c.542_543insT as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Still missing
  • No clinical laboratory benign assertions available
PS5 No established pathogenic variant at the same amino acid position has been identified for comparison. This is a frameshift variant, for which the PS5 framework (designed for missense substitutions) is not directly applicable. Details ▾Hide ▴
Still missing
  • No pathogenic variant at residue Ser182 available for comparison

Not assessed · 4 · no assessment recorded

PS3 OncoKB annotates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect based on curated literature. However, the three OncoKB-cited publications (PMID:17020408, PMID:24142871, PMID:24322982) discuss KEAP1 functional biology and somatic cancer mutations generally but do not mention NM_012289.4:c.542_543insT or provide variant-specific functional validation. No primary functional study demonstrating a damaging effect of this exact variant was identified. Details ▾Hide ▴
Evidence considered
  • OncoKB somatic annotation: Likely Oncogenic
  • Likely Loss-of-function (based on curated literature
  • not primary variant-specific functional assay)
Still missing
  • No variant-specific in vitro or in vivo functional studies demonstrating damaging effect on KEAP1 protein function
  • Full-text of PMID:17020408
  • PMID:24142871
  • PMID:24322982 not available for direct variant mention confirmation
Sources
oncokb ↗170204082414287124322982
PP3 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. HCI Prior is not available for KEAP1. Without multiple lines of computational evidence supporting a deleterious effect, PP3 cannot be applied for this insertion variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no predicted splice impact
Still missing
  • No in silico missense predictors available for insertion variants
Sources
spliceai ↗
BS3 The three OncoKB-cited publications (PMID:17020408, PMID:24142871, PMID:24322982) discuss KEAP1 functional biology and somatic cancer mutations but do not mention NM_012289.4:c.542_543insT in their abstracts. Full-text was not available for verification. OncoKB annotation of Likely Loss-of-function is inconsistent with benign functional evidence. No variant-specific functional studies demonstrating no damaging effect were identified. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies demonstrating no damaging effect
  • Full-text not available for PMID:17020408
  • PMID:24142871
  • PMID:24322982
Sources
170204082414287124322982
BP4 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. Without multiple lines of computational evidence predicting no impact, BP4 cannot be applied for this frameshift insertion variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no predicted splice impact
Still missing
  • No in silico predictors available for frameshift insertion variants
Sources
spliceai ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to nucleotide substitutions producing the same amino acid change as an established pathogenic missense variant. This variant is a frameshift insertion, not a nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per case instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to non-frameshift protein length changes (in-frame deletions/insertions in nonrepeat regions or stop-loss variants). NM_012289.4:c.542_543insT is a frameshift insertion covered by PVS1; applying PM4 would double-count the same molecular evidence. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AUnable to confirm classic same-residue PM5 semantics for a frameshift insertion. No same-residue comparator variants identified in ClinVar or via automated candidate harvesting. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to genes where missense variants are a common disease mechanism with a low rate of benign missense variation. KEAP1 is not established as such a gene, and this variant is a frameshift, not a missense. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where a different missense mechanism causes disease and truncating variants are the predominant pathogenic mechanism. NM_012289.4:c.542_543insT is a frameshift truncating variant, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_012289.4:c.542_543insT is a frameshift insertion, not an in-frame variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_012289.4:c.542_543insT is a frameshift insertion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
KEAP1
Transcript
NM_012289.4
Coding (HGVS c.)
NM_012289.4:c.542_543insT
Protein (HGVS p.)
NP_036421.2:p.(Ser182GlnfsTer11)
GRCh38
chr19:10499491 G>GA
GRCh37
chr19:10610167 G>GA

Gene diagram

Every interpreted variant in KEAP1, mapped onto the exon structure of NM_012289.4. Select a row to find it on the plot.

KEAP1NM_012289.4
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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. HCI Prior is not available for KEAP1. Without multiple lines of computational evidence supporting a deleterious effect, PP3 cannot be applied for this insertion variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no predicted splice impact
Still missing
  • No in silico missense predictors available for insertion variants
Sources
spliceai ↗
BP4 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion variants. Without multiple lines of computational evidence predicting no impact, BP4 cannot be applied for this frameshift insertion variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI: max delta score = 0.00
  • no predicted splice impact
Still missing
  • No in silico predictors available for frameshift insertion variants
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_012289.4:c.542_543insT is a frameshift insertion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

3 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

  • Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer.
    No paper-specific finding is recorded.
    PMID 17020408 ↗
  • The emerging role of the Nrf2-Keap1 signaling pathway in cancer.
    No paper-specific finding is recorded.
    PMID 24142871 ↗
  • Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination.
    No paper-specific finding is recorded.
    PMID 24322982 ↗

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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.