NM_002467.5:c.212_214dupTGC

MYC · NP_002458.2:p.(Leu71dup) · NM_002467.5

GRCh37: chr8:128750669 A>AGCT · GRCh38: chr8:127738423 A>AGCT

Gene: MYC Transcript: NM_002467.5

Final call

VUS

PM2 supporting PM4 moderate

Variant details

Gene

MYC

Transcript

NM_002467.5

Protein

NP_002458.2:p.(Leu71dup)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada (observed allele frequency 0).

PM4 (Moderate): in-frame 3-nt duplication adds one amino acid (454 to 455) outside repeat regions.

Synthesis: 1 moderate + 1 supporting does not meet any ACMG/AMP 2015 Pathogenic or Benign threshold, yielding Variant of Uncertain Significance.

Final determination: Under the generic ACMG/AMP 2015 fallback combination rules (no MYC VCEP/CSPEC exists), the adjudicated evidence (PM4 moderate + PM2 supporting) does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Variant of Uncertain Significance.

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: the in-frame Leu71dup is not a null variant, so no loss-of-function mechanism (nonsense-mediated decay, truncation) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no altered amino acid exists to compare against a previously established pathogenic change at this position.	generic_acmg_combination_rules
PS2	Not assessed	Insufficient evidence: no proband, parental testing, or de novo observation was available for this variant.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Insufficient evidence: no variant-specific functional assay exists; OncoKB reports unknown oncogenic effect.	generic_acmg_combination_rules oncokb clinvar spliceai
PS4	Not met	Not met: no case-control or enrichment data exists — only 2 somatic COSMIC observations, which are not germline evidence.	generic_acmg_combination_rules clinvar oncokb gnomad_v2 gnomad_v4 gnomad_canada
PM1	N/A	Not applicable: no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — observed allele frequency 0, below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Insufficient evidence: no affected proband, no pathogenic variant in trans, and no phase information.	clinvar gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context pm5_candidates generic_acmg_combination_rules
PM4	Met	Met (moderate): in-frame 3-nt duplication lengthens the protein by one amino acid (454 to 455) outside repeat regions.	generic_acmg_combination_rules pvs1_variant_assessment spliceai
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Insufficient evidence: no de novo observation (unconfirmed parental identity) was available.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Insufficient evidence: no pedigree, family history, or segregation data was available.	clinvar generic_acmg_combination_rules
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are irrelevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.02 is far below the 0.2 splice-altering threshold, and missense predictors do not apply to this variant class.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Insufficient evidence: no proband phenotype or family history data was available to evaluate specificity.	generic_acmg_combination_rules clinvar oncokb
PP5	Not met	Not met: the variant has no ClinVar record, so no expert-panel pathogenic classification exists to trigger PP5.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, orders of magnitude below the >1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: absent from all three population datasets (allele frequency 0), far below the >0.3% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: zero observations in gnomAD and ClinVar, so no healthy-adult carrier evidence exists.	gnomad_v2 gnomad_v4 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Insufficient evidence: no functional assay showing a lack of damaging effect; SpliceAI alone is not a functional study.	generic_acmg_combination_rules spliceai oncokb clinvar
BS4	Not assessed	Insufficient evidence: no family segregation or testing data exists; absence of data cannot count as non-segregation.	clinvar generic_acmg_combination_rules
BP1	N/A	Not applicable: no missense change is present, so the gene's truncating-variant mechanism is irrelevant.	generic_acmg_combination_rules
BP2	Not assessed	Insufficient evidence: no second variant, phase information, or inheritance data was available.	clinvar gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context pm5_candidates generic_acmg_combination_rules
BP3	Not met	Not met: the duplication lies outside canonical repeat regions, and the residue is in the functional transactivation domain.	generic_acmg_combination_rules pvs1_variant_assessment spliceai
BP4	Not met	Not met: a single low SpliceAI score (max delta 0.02) does not satisfy BP4's requirement of multiple computational lines.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Insufficient evidence: no genotype data beyond the index variant was available to evaluate an alternative molecular cause.	generic_acmg_combination_rules
BP6	Not met	Not met: the variant has no ClinVar record, so no expert-panel benign classification exists to trigger BP6.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: the variant alters protein sequence, so the synonymous-variant premise does not hold.	generic_acmg_combination_rules

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.