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NM_002467.5:c.212_214dup
p.Leu71dup · MYC
ACMG/AMP
0%
complete
Final classification
VUS
PM2PM4
MYC
c.212_214dup
p.Leu71dup
inframe insertion
Gene context NCBI Gene ↗ OncoKB ↗

MYC is a proto-oncogene that encodes a transcription factor central to cell cycle progression, apoptosis, and cellular transformation. It carries out its role by pairing with the protein MAX, and this complex regulates the expression of thousands of target genes. MYC is a well-established driver of cancer: the gene is frequently amplified in many human cancers, and its activity promotes tumor growth by driving cell proliferation, preventing cells from exiting the cell cycle, stimulating blood vessel formation, and enhancing genomic instability. Translocations involving MYC are also associated with Burkitt lymphoma and multiple myeloma.

This variant

MYC is a cancer driver typically altered by somatic amplification or translocation; this germline in-frame Leu71dup in the transactivation domain adds one amino acid but is absent from population databases. With no disease, functional, or benign evidence available, the variant cannot yet be assigned a pathogenic or benign role and remains a VUS.

Transcript
NM_002467.5
HGVS · transcript:coding
NM_002467.5:c.212_214dup
GRCh38
chr8:127738423 A>AGCT
GRCh37
chr8:128750669 A>AGCT
Generic ACMG/AMP 2015 rules apply (no MYC-specific framework); PM2 (supporting) + PM4 (moderate) = 1 moderate + 1 supporting, below all Pathogenic, Likely Pathogenic, and Benign thresholds, so the variant is VUS.
Classification rationale
PM2PM4 VUS
MYC c.212_214dup inframe insertion

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.

PM2 + PM4 → VUS
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.
Gene diagram · NM_002467.5 · variants mapped to exon structure
MYC NM_002467.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada — observed allele frequency 0, below the 0.1% threshold.
gnomAD v2.1 exome: variant absent (0 alleles at 8-128750669-A-AGCT, GRCh37)gnomAD v4.1 exome: variant absent (0 alleles at chr8-127738423-A-AGCT, GRCh38)gnomAD-Canada v1.0 (HostSeq genomes): variant absent (0 carriers)
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PM4 moderate Pathogenic
Met (moderate): in-frame 3-nt duplication lengthens the protein by one amino acid (454 to 455) outside repeat regions.
Normalized consequence (prefetch.json, Mutalyzer + VariantValidator concordant): NM_002467.5:c.212_214dupTGC -> c.212_214dup -> NP_002458.2:p.(Leu71dup); in-frame single-residue duplication; exon 2 (c.31-802); protein length +1 aa.SpliceAI (evidence.json): max delta score 0.02, DS_AG 0.02 - no predicted splice impact; operative consequence is the in-frame protein change, not altered splicing.UCSC hg19 RepeatMasker and genomicSuperDups (chr8:128,750,500-128,750,900): no repeat element and no segmental duplication overlapping the variant site (g.128750675_128750677dup).
spliceai ↗
Assessed · not applied · 9 not met · 10 not assessed
Pathogenic
PS2 Insufficient evidence: no proband, parental testing, or de novo observation was available for this variant.
PS3 Insufficient evidence: no variant-specific functional assay exists; OncoKB reports unknown oncogenic effect.
PS4 Not met: no case-control or enrichment data exists — only 2 somatic COSMIC observations, which are not germline evidence.
PM3 Insufficient evidence: no affected proband, no pathogenic variant in trans, and no phase information.
PM6 Insufficient evidence: no de novo observation (unconfirmed parental identity) was available.
PP1 Insufficient evidence: no pedigree, family history, or segregation data was available.
PP3 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.
PP4 Insufficient evidence: no proband phenotype or family history data was available to evaluate specificity.
PP5 Not met: the variant has no ClinVar record, so no expert-panel pathogenic classification exists to trigger PP5.
Benign
BA1 Not met: allele frequency is 0 in gnomAD v2.1, v4.1, and gnomAD-Canada, orders of magnitude below the >1% threshold.
BS1 Not met: absent from all three population datasets (allele frequency 0), far below the >0.3% threshold.
BS2 Not met: zero observations in gnomAD and ClinVar, so no healthy-adult carrier evidence exists.
BS3 Insufficient evidence: no functional assay showing a lack of damaging effect; SpliceAI alone is not a functional study.
BS4 Insufficient evidence: no family segregation or testing data exists; absence of data cannot count as non-segregation.
BP2 Insufficient evidence: no second variant, phase information, or inheritance data was available.
BP3 Not met: the duplication lies outside canonical repeat regions, and the residue is in the functional transactivation domain.
BP4 Not met: a single low SpliceAI score (max delta 0.02) does not satisfy BP4's requirement of multiple computational lines.
BP5 Insufficient evidence: no genotype data beyond the index variant was available to evaluate an alternative molecular cause.
BP6 Not met: the variant has no ClinVar record, so no expert-panel benign classification exists to trigger BP6.
N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYC, a transcription factor, is altered by chromosomal rearrangement, amplification and overexpression in a variety of cancer types.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99419973, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots