Variant classification summary

NM_001987.4:c.1204T>G

ETV6 · NP_001978.1:p.(Tyr402Asp) · NM_001987.4

GRCh37: chr12:12038911 T>G · GRCh38: chr12:11885977 T>G

Gene: ETV6 Transcript: NM_001987.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ETV6

Transcript

NM_001987.4

Protein

NP_001978.1:p.(Tyr402Asp)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, indicating extreme rarity in population databases.

2

PP3 (Supporting): REVEL score 0.855 exceeds the ~0.7 pathogenic-supporting threshold, indicating a deleterious missense effect.

3

With only two supporting-strength criteria (PM2, PP3) and no benign criteria met, the variant is classified as a variant of uncertain significance under the generic ACMG/AMP 2015 combination rules.

Final determination: 1 PM (supporting) + 1 PP (supporting) does not meet any generic ACMG threshold for LP/P/LB/B, so the variant is VUS.

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	N/A	Not applicable: this missense change does not belong to the null-variant classes (nonsense, frameshift, splice-site, start-loss, stop-loss) that PVS1 covers.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no ClinVar record or other nucleotide change producing the same p.Tyr402Asp amino acid with an established pathogenic classification was found.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype or parental genotype data were provided, so de novo occurrence cannot be established.
PS3	Not assessed	Not assessed: no functional assay data (e.g., DNA-binding or transcriptional assays) for this variant were available.
PS4	Not assessed	Not assessed: no case-control or case-enrichment data for this variant were available.
PM1	Not assessed	Not assessed: no citable mutational-hotspot or functional-domain boundary evidence for residue 402 was available.
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, indicating extreme rarity.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no second ETV6 variant or phase information was available to establish a pathogenic variant in trans.	final_classification_framework
PM4	N/A	Not applicable: this missense change does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate amino acid substitution at codon 402 with an established pathogenic ClinVar classification was found.	pm5_candidates
PM6	Not assessed	Not assessed: no reported de novo occurrence or parental testing was provided.
PP1	Not assessed	Not assessed: no pedigree or segregation data (informative meioses) were provided.
PP2	Not assessed	Not assessed: no gene-level missense constraint metric (e.g., gnomAD Z-score) was available for ETV6.
PP3	Met	Met (supporting): REVEL score 0.855 exceeds the ~0.7 pathogenic-supporting threshold, supporting a deleterious missense effect.	revel
PP4	Not assessed	Not assessed: no proband phenotype or variant-specific clinical report was provided.
PP5	Not assessed	Not assessed: ClinVar holds no record for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency approaches a stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no allele frequency above the ETV6-disease threshold was observed in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no homozygotes or unaffected adult carriers were observed in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data showing normal activity for this variant were available.
BS4	Not assessed	Not assessed: no relative genotype-phenotype observations were provided from which non-segregation could be shown.
BP1	Not assessed	Not assessed: no evidence established that missense variants are depleted among pathogenic ETV6 alleles.
BP2	Not assessed	Not assessed: no observation of this variant in cis with a pathogenic ETV6 variant, or homozygous in an unaffected individual.	final_classification_framework
BP3	N/A	Not applicable: this missense change is not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.855 predicts a deleterious effect, the opposite of the benign prediction BP4 requires.	revel
BP5	Not assessed	Not assessed: no independent molecular diagnosis was provided to assess an alternative disease cause.
BP6	Not assessed	Not assessed: ClinVar holds no record for this exact variant.	clinvar
BP7	N/A	Not applicable: this is a missense change, not a synonymous variant.	generic_acmg_combination_rules

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