Variant classification summary

NM_005378.5:c.926G>T

MYCN · NP_005369.2:p.(Gly309Val) · NM_005378.5

GRCh37: chr2:16085750 G>T · GRCh38: chr2:15945628 G>T

Gene: MYCN Transcript: NM_005378.5

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

MYCN

Transcript

NM_005378.5

Protein

NP_005369.2:p.(Gly309Val)

gnomAD AF

1.8586139943721168e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): variant is extremely rare in gnomAD v4.1 (3/1,614,106 alleles, AF 0.00019%) with no homozygotes.

2

BP4 (Supporting): REVEL score 0.214 falls at or below the 0.290 supporting threshold.

3

Classification: VUS — PM2 (Moderate) plus BP4 (Supporting) does not meet any ACMG/AMP 2015 pathogenic or benign threshold.

Final determination:

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: this is a 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 ClinVar record exists and no other nucleotide change producing the same p.Gly309Val amino acid change was found.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or parentage confirmation were provided, so de novo occurrence cannot be established.
PS3	Not assessed	Not assessed: no functional assay evidence for p.Gly309Val (transcriptional activity, dimerization, or proliferation) was identified.
PS4	Not assessed	Not assessed: no case-control or case-enrichment evidence for this variant was supplied.
PM1	Not assessed	Not assessed: residue Gly309 falls in no known mutational hotspot or characterized functional domain of MYCN.	oncokb pvs1_gene_context
PM2	Met	Met (Moderate): extremely rare in gnomAD v4.1 — 3/1,614,106 alleles (AF 0.00019%), zero homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no pathogenic variant in trans was identified, and MYCN-related Feingold syndrome is autosomal dominant.
PM4	N/A	Not applicable: this missense substitution does not alter protein length, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate pathogenic missense change at codon 309 was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no report of a de novo occurrence without confirmed parentage was provided.
PP1	Not assessed	Not assessed: no affected or unaffected relatives with genotypes were reported, so cosegregation cannot be evaluated.
PP2	Not assessed	Not assessed: MYCN missense pathogenicity is position-dependent, and no gene-level missense constraint statistic was available.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.214 falls well below the 0.644 supporting-pathogenic threshold.	revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype or diagnostic context was available for this variant.
PP5	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: highest observed frequency is 0.00669% (East Asian gnomAD v4.1), far below the stand-alone benign threshold.	gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: highest observed frequency 0.00669% is not above the expected frequency for a rare dominant developmental disorder.	gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no homozygotes and no phenotype or age data showing occurrence in unaffected adults.	gnomad_v4
BS3	Not assessed	Not assessed: no functional assay demonstrating normal activity for p.Gly309Val was identified.
BS4	Not assessed	Not assessed: no informative non-segregation observations were reported.
BP1	N/A	Not applicable: missense variation is an established disease mechanism in MYCN (gain-of-function phosphodegron variants), not tolerated background.	pvs1_gene_context
BP2	Not assessed	Not assessed: no observation of this variant in cis or trans with a pathogenic variant was identified.
BP3	N/A	Not applicable: this missense substitution does not alter protein length in a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): REVEL score 0.214 falls at or below the 0.290 BP4-supporting threshold.	revel spliceai
BP5	Not assessed	Not assessed: no evidence this variant was observed alongside an alternative cause of disease.
BP6	Not met	Not met: ClinVar has no exact-variant record, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant premise does not hold.	generic_acmg_combination_rules

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