Variant classification summary

NM_002467.6:c.221C>G

MYC · NP_002458.2:p.(Pro74Arg) · NM_002467.6

GRCh37: chr8:128750684 C>G · GRCh38: chr8:127738438 C>G

Gene: MYC Transcript: NM_002467.6

Final call

VUS

PM1 supporting PM2 moderate PP3 supporting

Variant details

Gene

MYC

Transcript

NM_002467.6

Protein

NP_002458.2:p.(Pro74Arg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Supporting): curated 'Likely Oncogenic' change at residue 74, a recurrent hotspot in the MYC N-terminal transactivation region near the T58/S62 phosphodegron.

2

PM2 (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, indicating rarity in reference populations.

3

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

4

Overall: VUS — 1 moderate + 2 supporting criteria meet no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Generic ACMG/AMP 2015 fallback rules require at minimum (1 PVS1 + 1 PM) or (1 PS + 1 PM) or (3 PM) or (2 PM + 2 PP) or (1 PM + 4 PP) for Likely Pathogenic, or higher combinations for Pathogenic, and (1 BS + 1 BP) or (2 BP) for Likely Benign; 1 moderate + 2 supporting meets none of these thresholds, 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: missense substitution, so no null-variant mechanism (nonsense-mediated decay, truncation, or splice disruption) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously classified pathogenic variant producing the identical p.Pro74Arg change was available.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no parental testing or pedigree evidence of confirmed de novo occurrence was available.
PS3	Not assessed	Not assessed: no validated functional assay data for p.Pro74Arg were available; OncoKB's label is curation, not assay evidence.
PS4	Not assessed	Not assessed: no affected-proband counts or case-control enrichment data were identified.
PM1	Met	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
PM2	Met	Met (Moderate): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in reference populations.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations or evidence of a pathogenic variant in trans were available.
PM4	N/A	Not applicable: missense substitution, so no in-frame indel or stop-loss protein-length change occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at codon 74 previously established as pathogenic was available.	pm5_candidates
PM6	Not assessed	Not assessed: no case-level evidence of suspected de novo occurrence without confirmed parentage was available.
PP1	Not assessed	Not assessed: no familial segregation data for this variant were available.
PP2	Not assessed	Not assessed: no MYC missense-constraint metric and no established germline missense disease mechanism.	pvs1_gene_context
PP3	Met	Met (Supporting): REVEL 0.721 falls in the calibrated PP3-supporting band (0.644-0.773), predicting a damaging missense effect.	revel
PP4	Not assessed	Not assessed: no patient phenotype or phenotype-to-gene specificity information was provided.
PP5	Not assessed	Not assessed: variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: no allele frequency was observed in population databases, so no benign frequency threshold is approached.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy adult homozygotes or unaffected carriers were observed in population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data showing normal or wild-type-like behavior for p.Pro74Arg were available.
BS4	Not assessed	Not assessed: no non-segregation evidence from tested unaffected relatives was available.
BP1	Not met	Not met: the curated 'Likely Oncogenic' gain-of-function status is inconsistent with a gene whose missense variants are generally benign.	oncokb
BP2	Not assessed	Not assessed: no evidence of a pathogenic variant in trans or cis was available.
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.721 falls in the pathogenic-supporting band, so a benign computational prediction cannot also apply.	spliceai revel
BP5	Not assessed	Not assessed: no affected patient with an alternative molecular etiology was provided.
BP6	Not assessed	Not assessed: variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: missense substitution, so the silent-variant (synonymous) premise does not apply.	generic_acmg_combination_rules

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