Classification rationale

PM2 BP4 VUS

MYCN c.1069C>T

PM2 (supporting): This variant is present at extremely low frequency in gnomAD v4.1 (3/1,614,110 alleles, AF=0.00019%, no homozygotes), highest in European non-Finnish (3/1,180,022), and absent from gnomAD v2.1 and gnomAD-Canada.¹ BP4 (supporting): Multiple in silico predictors suggest no deleterious effect — REVEL 0.26 (below 0.5 pathogenic threshold), BayesDel -0.326 (negative/benign), and SpliceAI max delta 0.00 (no predicted splicing impact).²

PM2 + BP4 → VUS

1 gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

Gene diagram · NM_005378.6 · variants mapped to exon structure

MYCN NM_005378.6

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Extremely low frequency in population databases: present in gnomAD v4.1 at 3/1,614,110 alleles (AF=0.00019%, no homozygotes), highest in European non-Finnish (3/1,180,022); absent from gnomAD v2.1 and gnomAD-Canada. Well below the 0.1% PM2 threshold.

gnomAD v4.1: 3/1614110 alleles (AF=1.86e-06

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no impact on gene product: REVEL 0.26 (below 0.5 pathogenic threshold), BayesDel -0.326 (negative/benign), SpliceAI max delta 0.00 (no predicted splicing alteration).

REVEL 0.26BayesDel -0.326SpliceAI max delta 0.00.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic missense variant at codon 357 has been reported in ClinVar or the literature.

PS2 No de novo data available for this variant.

PS3 No variant-specific functional studies identified.

PS4 No case-control or prevalence data available; variant absent from ClinVar.

PM1 Residue 357 is not in a statistically significant cancer hotspot; cancerhotspots.org returned no significance.

PM5 No pathogenic missense variant at codon 357 identified; PM5 candidate harvesting returned zero candidates.

PM6 No de novo data available for this variant.

PP1 No co-segregation data available for this variant.

PP2 Missense constraint data (z-score) for MYCN not available in evidence sources.

PP3 Multiple computational predictors suggest a benign effect: REVEL 0.26 (below 0.5 pathogenic threshold), BayesDel -0.326 (negative/benign), SpliceAI max delta 0.00 (no predicted splicing impact).

PP4 No patient phenotype or family history data provided for assessment.

PP5 Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.

Benign

BA1 gnomAD v4.1 allele frequency is 0.00019%, far below the 1% BA1 threshold.

BS1 gnomAD v4.1 allele frequency is 0.00019%, below the 0.3% BS1 threshold.

BS2 No data on observation in healthy adults; MYCN-associated conditions are fully penetrant autosomal dominant disorders.

BS3 No in vitro or in vivo functional studies demonstrating no deleterious effect for this variant.

BS4 No non-segregation data available for this variant.

BP1 While Feingold syndrome type 1 is primarily caused by MYCN truncating variants, pathogenic missense variants in MYCN have been reported in both Feingold syndrome (p.Ala152Thr, PMID:42195009) and megalencephaly-polydactyly syndrome (p.Thr58Met, p.Pro60Leu).

BP2 No data on observation in trans with a pathogenic variant; MYCN disorders are autosomal dominant.

BP5 No alternate molecular basis for disease identified; no case data available.

BP6 Variant is absent from ClinVar; no reputable source has reported this variant as benign.

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85861e-06; MAF= 0.00019%, 3/1614110 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54233e-06; MAF= 0.00025%, 3/1180022 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

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

0.00019% · 3 / 1,614,110
0 hom · FAF 6.8e-05%

European (non-Finnish)

3 / 1,180,022

0.00025%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 = 0.26. BayesDel score = -0.326084.

SpliceAI ↗

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. MYCN, a transcription factor, is altered by amplification and overexpression in a variety of cancer types including in neuroblastoma.

OncoKB ↗

COSMIC

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; COSV99807954, n = 3 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