Classification rationale

PM2 BP4 VUS

MYCN c.368G>T missense · exon 2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with zero alleles across 1,599,516. BP4 (Supporting): REVEL 0.216 falls at/below the <=0.290 benign-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact. One supporting pathogenic criterion opposed by one supporting benign criterion satisfies no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule; the variant is classified as VUS.

PM2 + BP4 → VUS

Gene diagram · NM_005378.5 · variants mapped to exon structure

MYCN NM_005378.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 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 · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with zero alleles across 1,599,516.

The variant is absent from gnomAD v2.1.gnomAD v4.1 reports total AC=0, AN=1,599,516, AF=0.0, and total homozygotes=0; the maximum listed ancestry-specific AF is also 0.0.The variant is absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.216 meets the <=0.290 benign-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact.

REVEL score = 0.216 for NM_005378.5:c.368G>T (p.Arg123Leu), at/below the ClinGen SVI Pejaver et al. 2022 (PMID 36413997) benign-supporting threshold of <=0.290, supporting BP4 at supporting strength.SpliceAI predicts no significant splice impact for this variant (max delta score = 0.003; DS_AG=0.0, DS_AL=0.003, DS_DG=0.0, DS_DL=0.0), consistent with no disruption of splicing and supporting BP4.No ClinGen VCEP-specific PP3/BP4 lookup table or gene-specific in-silico framework is available for MYCN in this case (framework_mode = generic_acmg; cspec.found = false), so generic calibrated thresholds were applied instead.

spliceai ↗

Assessed · not applied · 4 not met · 18 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to determine whether p.Arg123Leu matches a known pathogenic amino acid change.

PS2 Not assessed: no parental testing or trio data were available to confirm a de novo origin.

PS3 Not assessed: no functional assay data for p.Arg123Leu were identified, so a damaging effect could not be established.

PS4 Not assessed: no germline case-control or affected-case data exist; the single somatic COSMIC record does not qualify.

PM1 Not assessed: insufficient evidence was available to determine whether p.Arg123Leu lies in a mutational hotspot or critical domain.

PM3 Not assessed: no affected proband or phase data showing a pathogenic variant in trans were available.

PM5 Not assessed: insufficient evidence was available to determine whether a different pathogenic missense occurs at this same codon.

PM6 Not assessed: no presumed de novo occurrence was documented.

PP1 Not assessed: no affected relatives or informative meioses were documented, so cosegregation could not be evaluated.

PP2 Not assessed: insufficient evidence was available on MYCN's rate of benign missense variation.

PP3 Not met: REVEL 0.216 is below the 0.644 pathogenic-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact.

PP4 Not assessed: the patient's phenotype and its specificity for MYCN-related disease were not provided.

PP5 Not assessed: no ClinVar expert-panel pathogenic classification exists for this exact variant.

Benign

BA1 Not met: allele frequency is 0 in 1,599,516 gnomAD v4.1 alleles, far below the >5% stand-alone benign threshold.

BS1 Not met: the variant is absent from population databases, not present at a frequency exceeding that expected for a pathogenic MYCN variant.

BS2 Not met: no healthy carriers or homozygous healthy individuals were observed in the population datasets.

BS3 Not assessed: no functional assay data showing normal activity for p.Arg123Leu were available.

BS4 Not assessed: no unaffected relatives were tested, so non-segregation could not be evaluated.

BP1 Not assessed: insufficient evidence was available to determine whether MYCN loss-of-function is the sole disease mechanism.

BP2 Not assessed: no phase or co-occurrence data showing the variant in trans with a benign or in cis with a pathogenic variant were available.

BP5 Not assessed: no confirmed alternate molecular etiology for the patient's phenotype was provided.

BP6 Not assessed: no ClinVar expert-panel benign classification exists for this exact variant.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1599516 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74962 alleles, homozygotes = 0).

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 / 1,599,516
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

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 = 0.216. BayesDel score = -0.349224.

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; COSV107256617, n = 1 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