Classification rationale

PM1PM2PP3 VUS

MYC c.221C>G missense · exon 2

PM1 (Supporting): curated 'Likely Oncogenic' change at residue 74, a recurrent hotspot in the MYC N-terminal transactivation region near the T58/S62 phosphodegron. PM2 (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating rarity in reference populations. PP3 (Supporting): REVEL 0.721 falls in the PP3-supporting band (0.644-0.773), predicting a damaging missense effect. Overall: VUS — 1 moderate + 2 supporting criteria meet no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

PM1 + PM2 + PP3 → VUS

Gene diagram · NM_002467.6 · variants mapped to exon structure

MYC NM_002467.6

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 21 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 · 3

Strength Supporting Moderate Strong Very strong

✓

PM1 supporting review Pathogenic

Met (Supporting): OncoKB curation flags p.Pro74Arg as likely oncogenic, a recurrent change in the MYC N-terminal transactivation region near the T58/S62 phosphodegron hotspot.

OncoKB variant-specific page for MYC P74R (https://www.oncokb.org/gene/MYC/P74R) reports classification 'Likely Oncogenic' and biological_effect 'Likely Gain-of-function', explicitly is_variant_specific=true (not a gene-level summary).Case evidence.json (not independently citable) additionally records cancerhotspots.org flagging P74 as 'a statistically significant hotspot' and COSMIC recording 5 somatic occurrences of this exact change (COSV52375206) — used only as corroborating context, not as a formal evidence_ref.

oncokb ↗

✓

PM2 moderate review Pathogenic

Met (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in reference populations.

The case bundle reports the exact variant as absent from gnomAD v2.1.The case bundle reports the exact variant as absent from gnomAD v4.1.The case bundle reports the exact variant as absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

Met (Supporting): REVEL 0.721 falls in the calibrated PP3-supporting band (0.644-0.773), predicting a damaging missense effect.

REVEL score = 0.721 for NM_002467.6:c.221C>G (local REVEL v1.3 lookup), which falls in the PP3_Supporting range (>=0.644, <0.773) of the ClinGen SVI-recommended calibrated REVEL thresholds published by Pejaver et al. 2022 (PMID 36413997).SpliceAI max delta score = 0.00 (pangolin_SG=0.002, pangolin_SL=-0.004) indicates no predicted splice-altering effect, consistent with the variant acting through a missense mechanism rather than splicing; this observation was not separately counted toward PP3/BP4/BP7 to avoid double counting.No ClinGen MYC VCEP-specific PP3/BP4 lookup table was found (cspec.found=false; vcep_materials.summaries empty), so the generic ACMG/AMP REVEL-based approach was applied.

Assessed · not applied · 4 not met · 17 not assessed

Pathogenic

PS1 Not assessed: no previously classified pathogenic variant producing the identical p.Pro74Arg change was available.

PS2 Not assessed: no parental testing or pedigree evidence of confirmed de novo occurrence was available.

PS3 Not assessed: no validated functional assay data for p.Pro74Arg were available; OncoKB's label is curation, not assay evidence.

PS4 Not assessed: no affected-proband counts or case-control enrichment data were identified.

PM3 Not assessed: no affected-proband observations or evidence of a pathogenic variant in trans were available.

PM5 Not assessed: no different missense change at codon 74 previously established as pathogenic was available.

PM6 Not assessed: no case-level evidence of suspected de novo occurrence without confirmed parentage was available.

PP1 Not assessed: no familial segregation data for this variant were available.

PP2 Not assessed: no MYC missense-constraint metric and no established germline missense disease mechanism.

PP4 Not assessed: no patient phenotype or phenotype-to-gene specificity information was provided.

PP5 Not assessed: variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.

Benign

BA1 Not met: variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% stand-alone benign threshold.

BS1 Not met: no allele frequency was observed in population databases, so no benign frequency threshold is approached.

BS2 Not assessed: no healthy adult homozygotes or unaffected carriers were observed in population datasets.

BS3 Not assessed: no functional assay data showing normal or wild-type-like behavior for p.Pro74Arg were available.

BS4 Not assessed: no non-segregation evidence from tested unaffected relatives was available.

BP1 Not met: the curated 'Likely Oncogenic' gain-of-function status is inconsistent with a gene whose missense variants are generally benign.

BP2 Not assessed: no evidence of a pathogenic variant in trans or cis was available.

BP4 Not met: REVEL 0.721 falls in the pathogenic-supporting band, so a benign computational prediction cannot also apply.

BP5 Not assessed: no affected patient with an alternative molecular etiology was provided.

BP6 Not assessed: variant is absent from ClinVar, so no expert-panel benign assertion exists.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.721. BayesDel score = 0.210026.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52375206, n = 5 times).

Hotspots

This variant lies 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

Triaged references · 1 PMID not cited in assessment

27276561 ↗ Genomic Classification and Prognosis in Acute Myeloid Leukemia. ONCOKB