Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
MYC
Final classification
VUS
MYC c.212_214dup · p.Leu71dup
MYC

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

Gene
MYC
Transcript
NM_002467.5
HGVS · transcript:coding
NM_002467.5:c.212_214dup
Consequence
N/A
GRCh38
chr8:127738423 A>AGCT
GRCh37
chr8:128750669 A>AGCT
Basis 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. ▾
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

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
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
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
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