NM_005378.6:c.1069C>T

MYCN · NP_005369.2:p.(Arg357Cys) · NM_005378.6

GRCh37: chr2:16085893 C>T · GRCh38: chr2:15945771 C>T

Gene: MYCN Transcript: NM_005378.6

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYCN

Transcript

NM_005378.6

Protein

NP_005369.2:p.(Arg357Cys)

gnomAD AF

1.8586093884555574e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination 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	Missense variant (p.Arg357Cys) does not meet PVS1 null-variant criteria; not a nonsense, frameshift, or canonical ±1,2 splice site variant.	pvs1_generic_framework
PS1	Not met	No established pathogenic missense variant at codon 357 has been reported in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not met	No de novo data available for this variant.
PS3	Not met	No variant-specific functional studies identified. REVEL (0.26) and BayesDel (-0.326) are computational predictions, not experimental functional evidence.	revel bayesdel oncokb
PS4	Not met	No case-control or prevalence data available; variant absent from ClinVar.	clinvar
PS5	N/A	Not a standard ACMG/AMP 2015 criterion; no applicable evidence framework for this code.
PM1	Not met	Residue 357 is not in a statistically significant cancer hotspot; cancerhotspots.org returned no significance. While position 357 lies near the C-terminal bHLH domain, no domain-level functional characterization specific to this residue has been established in the literature for this variant.
PM2	Met	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 gnomad_v2 gnomad_canada
PM5	Not met	No pathogenic missense variant at codon 357 identified; PM5 candidate harvesting returned zero candidates.	pm5_candidates clinvar
PM6	Not met	No de novo data available for this variant.
PP1	Not met	No co-segregation data available for this variant.
PP2	Not assessed	Missense constraint data (z-score) for MYCN not available in evidence sources. MYCN has both loss-of-function (Feingold syndrome, mostly truncating) and gain-of-function missense (megalencephaly-polydactyly) disease mechanisms. Cannot determine whether the gene has a low rate of benign missense variation without gnomAD constraint metrics.
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data provided for assessment.
PP5	Not met	Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.00019%, far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 0.00019%, below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not met	No data on observation in healthy adults; MYCN-associated conditions are fully penetrant autosomal dominant disorders.
BS3	Not met	No in vitro or in vivo functional studies demonstrating no deleterious effect for this variant. Computational predictions (REVEL 0.26, BayesDel -0.326) are not well-established functional assays.	revel bayesdel oncokb
BS4	Not met	No non-segregation data available for this variant.
BP1	Not met	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). BP1 is therefore not applicable.
BP2	Not met	No data on observation in trans with a pathogenic variant; MYCN disorders are autosomal dominant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease identified; no case data available.
BP6	Not met	Variant is absent from ClinVar; no reputable source has reported this variant as benign.	clinvar
BP7	N/A	Missense variant (p.Arg357Cys); BP7 applies only to synonymous or intronic variants without predicted splice effect.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.