NM_005378.5:c.368G>T

MYCN · NP_005369.2:p.(Arg123Leu) · NM_005378.5

GRCh37: chr2:16082554 G>T · GRCh38: chr2:15942432 G>T

Gene: MYCN Transcript: NM_005378.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYCN

Transcript

NM_005378.5

Protein

NP_005369.2:p.(Arg123Leu)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 combination rules require at least one strong/moderate pathogenic combination for a pathogenic-spectrum call, or 1BS+1BP/2BP for a benign-spectrum call; PM2(supporting)+BP4(supporting) alone meets neither and is conflicting in direction, so the variant defaults to VUS.

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) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to determine whether p.Arg123Leu matches a known pathogenic amino acid change.
PS2	Not assessed	Not assessed: no parental testing or trio data were available to confirm a de novo origin.
PS3	Not assessed	Not assessed: no functional assay data for p.Arg123Leu were identified, so a damaging effect could not be established.
PS4	Not assessed	Not assessed: no germline case-control or affected-case data exist; the single somatic COSMIC record does not qualify.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether p.Arg123Leu lies in a mutational hotspot or critical domain.
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with zero alleles across 1,599,516.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband or phase data showing a pathogenic variant in trans were available.
PM4	N/A	Not applicable: missense substitution causes no protein length change, so this in-frame indel/stop-loss criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether a different pathogenic missense occurs at this same codon.
PM6	Not assessed	Not assessed: no presumed de novo occurrence was documented.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses were documented, so cosegregation could not be evaluated.
PP2	Not assessed	Not assessed: insufficient evidence was available on MYCN's rate of benign missense variation.
PP3	Not met	Not met: REVEL 0.216 is below the 0.644 pathogenic-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact.	revel spliceai
PP4	Not assessed	Not assessed: the patient's phenotype and its specificity for MYCN-related disease were not provided.	oncokb
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: allele frequency is 0 in 1,599,516 gnomAD v4.1 alleles, far below the >5% stand-alone benign threshold.	gnomad_v4
BS1	Not met	Not met: the variant is absent from population databases, not present at a frequency exceeding that expected for a pathogenic MYCN variant.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no healthy carriers or homozygous healthy individuals were observed in the population datasets.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data showing normal activity for p.Arg123Leu were available.
BS4	Not assessed	Not assessed: no unaffected relatives were tested, so non-segregation could not be evaluated.
BP1	Not assessed	Not assessed: insufficient evidence was available to determine whether MYCN loss-of-function is the sole disease mechanism.
BP2	Not assessed	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.
BP3	N/A	Not applicable: missense substitution does not alter protein length, so this in-frame indel criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.216 meets the <=0.290 benign-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact.	revel spliceai
BP5	Not assessed	Not assessed: no confirmed alternate molecular etiology for the patient's phenotype was provided.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: missense substitution, so the silent-variant premise of this criterion does not hold.	generic_acmg_combination_rules

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