NM_005378.6:c.553G>A

MYCN · NP_005369.2:p.(Glu185Lys) · NM_005378.6

GRCh37: chr2:16082739 G>A · GRCh38: chr2:15942617 G>A

Gene: MYCN Transcript: NM_005378.6

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MYCN

Transcript

NM_005378.6

Protein

NP_005369.2:p.(Glu185Lys)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): NM_005378.6:c.553G>A (p.Glu185Lys) is absent from gnomAD v2.1 and v4.1 (0/1,113,262 alleles), consistent with extremely low population frequency.

BP4 (supporting benign): Multiple in silico tools predict no significant impact — BayesDel score -0.415 (benign) and SpliceAI max delta 0.01 (no splicing alteration). REVEL score 0.334 is intermediate.

At present the available evidence is conflicting: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868), this yields a Variant of Uncertain Significance (VUS). Critical missing evidence includes functional studies of the variant, de novo or segregation data, and variant-specific clinical reports.

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	This is a missense variant (c.553G>A, p.Glu185Lys). The generic PVS1 framework (PMC6185798) applies only to null variants (nonsense, frameshift, or canonical ±1,2 splice consensus); this missense substitution does not fall into any PVS1 null-variant bucket.	pvs1_generic_framework
PS1	Not met	No established pathogenic variant with the same amino acid change (p.Glu185Lys) at this position has been identified in ClinVar or the published literature.	clinvar
PS2	Not assessed	No de novo data (confirmed or unconfirmed parentage) are available for this variant.
PS3	Not met	No published functional studies have directly tested NM_005378.6:c.553G>A (p.Glu185Lys). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. In silico predictors are equivocal (REVEL 0.334, BayesDel -0.415) and do not substitute for experimental functional data.	oncokb revel bayesdel
PS4	Not assessed	No case-control or statistical enrichment data available for this variant.
PS5	Not assessed	No data on this variant observed in trans with a pathogenic variant for a recessive disorder. MYCN is an autosomal dominant disease gene.
PM1	Not met	Residue Glu185 is not located in a statistically significant mutational hotspot (cancerhotspots.org) and is not within a well-established critical functional domain where missense variants are known to be recurrently pathogenic. Known MYCN gain-of-function missense mutations cluster at T58/P60 in the N-terminal degron; this variant lies outside those regions.	oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and v4.1 (0/1,113,262 alleles; allele frequency <0.1%), consistent with absent or extremely rare population frequency.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No ClinVar pathogenic variant at the same amino acid residue (Glu185) with a different amino acid change was identified. Automatic PM5 candidate harvesting returned no candidates.	pm5_candidates
PM6	Not assessed	No de novo observation data (confirmed or unconfirmed parentage) are available for this variant.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members are available for this variant.
PP2	Not assessed	Missense constraint metrics (e.g., Z-score, gnomAD missense constraint, HCI prior) are not available for MYCN in the case data. Although MYCN missense variants are a known mechanism of disease (both LoF in FS1 and GoF in MPS), PP2 requires quantitative evidence of low benign missense variation in the gene.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.334 (intermediate, below typical pathogenic threshold), BayesDel score is -0.415 (benign prediction), and SpliceAI predicts no splicing impact (max delta 0.01). Multiple computational tools do not concordantly predict pathogenicity.	revel bayesdel spliceai
PP4	Not assessed	No phenotype or family history data specific to this variant are available. The patient's clinical presentation has not been provided.
PP5	Not assessed	This variant is absent from ClinVar; no reputable source has reported it as pathogenic or likely pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD v4.1 (0/1,113,262 alleles; AF = 0%). The allele frequency does not exceed the 1% threshold for BA1.	gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1 (0/1,113,262 alleles; AF = 0%). The allele frequency does not exceed the 0.3% threshold for BS1.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adults in the context of a fully penetrant early-onset disorder. MYCN-related Feingold syndrome is autosomal dominant with complete penetrance; healthy adult carriers would be informative but none have been reported.
BS3	Not assessed	No well-established in vitro or in vivo functional studies have been performed on this variant. In silico predictors are suggestive but do not constitute BS3-level functional evidence.
BS4	Not assessed	No segregation data are available for this variant; lack of segregation with disease cannot be evaluated.
BP1	Not met	BP1 applies when a missense variant is in a gene where only truncating variants cause disease. MYCN missense variants are an established disease mechanism: N-terminal LoF missense variants cause Feingold syndrome type 1 (e.g., A152T reported in PMID:42195009), and GoF missense variants (T58M, P60L) cause megalencephaly-polydactyly syndrome. MYCN-associated disease is not limited to truncating variants.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic MYCN variant (for dominant disorder) or in cis with a pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. BayesDel predicts a benign effect (score -0.415), and SpliceAI predicts no splicing alteration (max delta score 0.01). REVEL score (0.334) is intermediate but not strongly pathogenic. Two independent in silico tools concordantly support a benign or non-deleterious interpretation.	bayesdel spliceai revel
BP5	Not assessed	No data on this variant found in a case with an alternative molecular basis for disease.
BP6	Not assessed	This variant is absent from ClinVar; no reputable source has classified it as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.553G>A, p.Glu185Lys), not a synonymous variant. BP7 applies only to synonymous or intronic variants without predicted splice impact.

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.