Variant classification summary

NM_001987.4:c.133dup

ETV6 · NP_001978.1:p.(Glu45GlyfsTer21) · NM_001987.4

GRCh37: chr12:11905481 A>AG · GRCh38: chr12:11752547 A>AG

Gene: ETV6 Transcript: NM_001987.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

ETV6

Transcript

NM_001987.4

Protein

NP_001978.1:p.(Glu45GlyfsTer21)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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

3

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.

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to a different nucleotide change that results in the same amino acid substitution. This variant is a frameshift, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 cannot be assessed from the available evidence.	clinvar
PS3	Not assessed	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.	oncokb PMID:29455655
PS4	Not assessed	No enrichment data, case series, or multiple unrelated affected observations were identified for this variant, so PS4 cannot be applied.	clinvar
PM1	Not assessed	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.	hotspots PMID:29455655
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the <0.1% threshold used for PM2_supporting.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 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.
PM4	N/A	This 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.	pvs1_variant_assessment
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 cannot be assessed.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be applied.
PP2	N/A	PP2 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.
PP3	N/A	Computational 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.	spliceai
PP4	Not assessed	No individual phenotype or family history was provided that would allow assessment of whether the clinical presentation is highly specific for ETV6-related disease.
PP5	Not assessed	No independent reputable-source pathogenic classification for this exact variant was identified, so PP5 is not assessed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the >1% threshold required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the >0.3% threshold used for BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults with sufficient observations to support BS2.
BS3	Not assessed	No well-established functional study demonstrating a benign effect for this variant was identified, so BS3 cannot be applied.	oncokb PMID:29455655
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 cannot be applied.
BP1	N/A	BP1 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.
BP2	Not assessed	No phase information or co-occurrence data were identified for this variant, so BP2 cannot be assessed.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function. This variant is a frameshift and does not meet BP3 criteria.
BP4	N/A	Although 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.	spliceai
BP5	Not assessed	No alternate molecular diagnosis or independent cause for the phenotype was identified, so BP5 cannot be assessed.
BP6	Not assessed	No reputable-source benign classification for this exact variant was identified, so BP6 is not assessed.	clinvar
BP7	N/A	BP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a coding frameshift, so BP7 is not applicable.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.