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.1 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.2 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.3
MYCN
Final classification
VUS
MYCN c.553G>A · p.Glu185Lys
MYCN
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MYCN c.553G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_005378.6 · variants mapped to exon structure
MYCN
NM_005378.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (exomes)v4.1 (0/1113
✓
BP4
supporting
Benign
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 -0.415 (benign prediction)SpliceAI max delta 0.01 (no splice impact)REVEL 0.334 (intermediate).
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant with the same amino acid change (p.Glu185Lys) at this position has been identified in ClinVar or the published literature.
PS2
No de novo data (confirmed or unconfirmed parentage) are available for this variant.
PS3
No published functional studies have directly tested NM_005378.6:c.553G>A (p.Glu185Lys).
PS4
No case-control or statistical enrichment data available for this variant.
PM1
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.
PM6
No de novo observation data (confirmed or unconfirmed parentage) are available for this variant.
PP1
No co-segregation data with disease in multiple affected family members are available for this variant.
PP2
Missense constraint metrics (e.g., Z-score, gnomAD missense constraint, HCI prior) are not available for MYCN in the case data.
PP3
Multiple lines of in silico evidence do not support a deleterious effect.
PP4
No phenotype or family history data specific to this variant are available.
PP5
This variant is absent from ClinVar; no reputable source has reported it as pathogenic or likely pathogenic.
Benign
BA1
This variant is absent from gnomAD v4.1 (0/1,113,262 alleles; AF = 0%).
BS1
This variant is absent from gnomAD v4.1 (0/1,113,262 alleles; AF = 0%).
BS2
No data on observation of this variant in healthy adults in the context of a fully penetrant early-onset disorder.
BS3
No well-established in vitro or in vivo functional studies have been performed on this variant.
BS4
No segregation data are available for this variant; lack of segregation with disease cannot be evaluated.
BP1
BP1 applies when a missense variant is in a gene where only truncating variants cause disease.
BP2
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.
BP5
No data on this variant found in a case with an alternative molecular basis for disease.
BP6
This variant is absent from ClinVar; no reputable source has classified it as benign or likely benign.
N/A · 3
PVS1 · PM5 · 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%, 0/1113262 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/60432 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 / 1,113,262
0 hom
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
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = -0.415487.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links