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ETV6c.133dupLikely pathogenic
Print report
Variant interpretation report

ETV6 c.133dup, p.(Glu45GlyfsTer21)

NM_001987.4:c.133dup NP_001978.1:p.(Glu45GlyfsTer21) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ETV6

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

This variant is a frameshift change predicted as p.(Glu45GlyfsTer21) / p.(E45Gfs*21). Available gene-level evidence supports loss of function as a disease mechanism for ETV6, so this truncating variant meets generic PVS1 criteria.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the <0.1% threshold used for PM2_supporting.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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 Likely Pathogenic.

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
0.130 maximum delta

Recorded SpliceAI maximum delta score: 0.130. 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.

28 criteria with recorded statuses: 2 met · 2 not met · 14 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The ETV6 c.133dup (p.(Glu45GlyfsTer21), p.(E45Gfs*21)) variant has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the <0.1% threshold used for PM2_supporting.

ETV6 loss of function is supported as a germline disease mechanism, and this variant is an early frameshift predicted to truncate the protein, supporting PVS1 under the generic ClinGen SVI PVS1 framework.

Published literature curated through OncoKB supports the biological relevance of ETV6 loss of function, but no variant-specific functional assay for c.133dup was identified.

SpliceAI predicts no significant splice effect for this variant with a maximum delta score of 0.13, and no REVEL or BayesDel score is available for this frameshift variant.

Met · 2

PVS1 Very strongThis variant is a frameshift change predicted as p.(Glu45GlyfsTer21) / p.(E45Gfs*21). Available gene-level evidence supports loss of function as a disease mechanism for ETV6, so this truncating variant meets generic PVS1 criteria. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 fallback using ClinGen SVI PVS1 recommendations
Evidence considered
  • ETV6 loss of function is supported as a germline disease mechanism.
  • The variant is an early frameshift predicted to truncate the protein.
Still missing
  • No gene-specific PVS1 specification was available
  • this assessment uses the generic ClinGen SVI PVS1 framework.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the <0.1% threshold used for PM2_supporting. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 with supporting strength for rarity
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 2 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the >1% threshold required for BA1. Details ▾Hide ▴
Rule
Generic population threshold BA1 >1%
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the >0.3% threshold used for BS1. Details ▾Hide ▴
Rule
Generic population threshold BS1 >0.3%
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 14 · no assessment recorded

PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS2
Evidence considered
  • ClinVar search did not identify an exact variant record with inheritance data.
Still missing
  • No parental testing data were identified.
  • No exact-variant report documenting a confirmed de novo event was identified.
Sources
clinvar ↗
PS3 No published functional assay specific to this variant was identified. The retrieved literature addresses ETV6 disruption more broadly and does not provide direct functional evidence for c.133dup. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS3
Evidence considered
  • OncoKB linked curated literature for ETV6 loss-of-function context.
  • PMID:29455655 is gene-level and not a direct assay of c.133dup.
Still missing
  • No variant-specific functional study was identified.
Sources
oncokb ↗PMID:29455655 ↗
PS4 No enrichment data, case series, or multiple unrelated affected observations were identified for this variant, so PS4 cannot be applied. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS4
Evidence considered
  • ClinVar did not contain an exact variant record to support affected case counting.
Still missing
  • No case-control data were identified.
  • No count of unrelated affected individuals with this exact variant was identified.
Sources
clinvar ↗
PM1 Available evidence does not establish that this variant lies in a well-established mutational hotspot or a critical functional domain without benign variation, so PM1 is not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM1
Evidence considered
  • Cancer Hotspots did not identify a statistically significant hotspot at this residue.
  • Retrieved literature was not sufficient to define a PM1-eligible critical region for this variant.
Still missing
  • No curated critical-domain framework was available for ETV6.
  • Cancer Hotspots review did not provide definitive hotspot support.
Sources
hotspots ↗PMID:29455655 ↗
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM6
Evidence considered
  • ClinVar did not identify an exact variant record with de novo information.
Still missing
  • No inheritance report suggesting an assumed de novo event was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP1
Still missing
  • No pedigree or informative meiosis count was identified for this exact variant.
PP4 No individual phenotype or family history was provided that would allow assessment of whether the clinical presentation is highly specific for ETV6-related disease. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP4
Still missing
  • No phenotype description was available for PP4 review.
PP5 No independent reputable-source pathogenic classification for this exact variant was identified, so PP5 is not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP5
Evidence considered
  • ClinVar search was negative for this variant.
Still missing
  • No ClinVar classification or other exact-variant expert assertion was identified.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adults with sufficient observations to support BS2. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS2
Still missing
  • No healthy carrier dataset or adult observation evidence was identified.
BS3 No well-established functional study demonstrating a benign effect for this variant was identified, so BS3 cannot be applied. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS3
Evidence considered
  • Retrieved literature did not demonstrate a benign effect for c.133dup.
Still missing
  • No variant-specific benign functional assay was identified.
Sources
oncokb ↗PMID:29455655 ↗
BS4 No nonsegregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS4
Still missing
  • No family data showing lack of segregation with disease were identified.
BP2 No phase information or co-occurrence data were identified for this variant, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP2
Still missing
  • No in-trans or in-cis co-occurrence data were identified.
BP5 No alternate molecular diagnosis or independent cause for the phenotype was identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP5
Still missing
  • No phenotype-specific differential molecular diagnosis information was available.
BP6 No reputable-source benign classification for this exact variant was identified, so BP6 is not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP6
Evidence considered
  • ClinVar search was negative for this variant.
Still missing
  • No benign submitter classification or external exact-variant benign assertion was identified.
Sources
clinvar ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change that results in the same amino acid substitution. This variant is a frameshift, so PS1 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS1
Evidence considered
  • The variant consequence is frameshift
  • not a missense substitution.
PM3 N/APM3 is used for recessive disorders with pathogenic variants observed in trans. No recessive in-trans context was identified for this ETV6 variant, so PM3 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM3
PM4 N/AThis variant causes a frameshift with predicted protein truncation, and that loss-of-function effect is already captured by PVS1. PM4 is therefore not applied separately. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM4
Evidence considered
  • The variant consequence is frameshift.
Sources
pvs1_variant_assessment
PM5 N/APM5 applies to a novel missense change at a residue where another pathogenic missense change is established. This variant is a frameshift, and the available PM5 review did not support classic same-residue PM5 use. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM5
Evidence considered
  • The variant is not missense.
  • PM5 candidate review did not support classic same-residue PM5 semantics.
Sources
pm5_candidates
PP2 N/APP2 is primarily used for missense variants in genes with a low rate of benign missense variation and a mechanism driven by missense change. This frameshift variant is not eligible for PP2. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP2
Evidence considered
  • The variant consequence is frameshift
  • not missense.
PP3 N/AComputational missense predictors are not applicable to this frameshift variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.13. These in silico results do not provide separate pathogenic computational support. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP3
Evidence considered
  • SpliceAI max delta score is 0.13.
  • REVEL and BayesDel were not available for this non-SNV frameshift variant.
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is a truncating frameshift, so BP1 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP1
Evidence considered
  • The variant consequence is frameshift.
BP3 N/ABP3 applies to in-frame variants in repetitive regions without known function. This variant is a frameshift and does not meet BP3 criteria. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP3
Evidence considered
  • The variant is not an in-frame insertion or deletion.
BP4 N/AAlthough SpliceAI predicts no significant splice effect with a maximum delta score of 0.13, this does not provide benign computational evidence against the primary frameshift consequence. BP4 is therefore not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP4
Evidence considered
  • SpliceAI max delta score is 0.13.
  • The variant remains a truncating frameshift regardless of splice prediction.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP7
Evidence considered
  • The variant consequence is frameshift.

Identifiers

Gene
ETV6
Transcript
NM_001987.4
Coding (HGVS c.)
NM_001987.4:c.133dup
Protein (HGVS p.)
NP_001978.1:p.(Glu45GlyfsTer21)
GRCh38
chr12:11752547 A>AG
GRCh37
chr12:11905481 A>AG

Gene diagram

Every interpreted variant in ETV6, mapped onto the exon structure of NM_001987.4. Select a row to find it on the plot.

ETV6NM_001987.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

SpliceAI acceptor lossat -97 bp
0.130
SpliceAI acceptor gainat +121 bp
0.000
SpliceAI donor lossat +32 bp
0.100
SpliceAI donor gainat -94 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AComputational missense predictors are not applicable to this frameshift variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.13. These in silico results do not provide separate pathogenic computational support. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP3
Evidence considered
  • SpliceAI max delta score is 0.13.
  • REVEL and BayesDel were not available for this non-SNV frameshift variant.
Sources
spliceai ↗
BP4 N/AAlthough SpliceAI predicts no significant splice effect with a maximum delta score of 0.13, this does not provide benign computational evidence against the primary frameshift consequence. BP4 is therefore not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP4
Evidence considered
  • SpliceAI max delta score is 0.13.
  • The variant remains a truncating frameshift regardless of splice prediction.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP7
Evidence considered
  • The variant consequence is frameshift.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13).

1 paper record 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

  • Disruption of ETV6 leads to TWIST1-dependent progression and resistance to epidermal growth factor receptor tyrosine kinase inhibitors in prostate cancer.
    No paper-specific finding is recorded.
    PMID 29455655 ↗

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 0.130 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 = 0.13).

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.