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MYCNc.553G>AUncertain significance
Print report
Variant interpretation report

MYCN c.553G>A, p.(Glu185Lys)

NM_005378.6:c.553G>A NP_005369.2:p.(Glu185Lys) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MYCN

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 7 not met · 14 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • v4.1 (0/1
  • 113
  • 262 total alleles)
  • and gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel -0.415 (benign prediction)
  • SpliceAI max delta 0.01 (no splice impact)
  • REVEL 0.334 (intermediate).
Sources
bayesdelspliceai ↗revel

Not met · 7 · evaluated, threshold not reached

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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no pathogenic E185K comparator exists.
Still missing
  • No published functional or clinical data for this exact amino acid change.
Sources
clinvar ↗
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific functional data
  • REVEL 0.334 (intermediate)
  • BayesDel -0.415 (benign-leaning).
Still missing
  • No experimental functional studies of this variant.
Sources
oncokb ↗revelbayesdel
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. Known MYCN gain-of-function missense mutations cluster at T58/P60 in the N-terminal degron; this variant lies outside those regions. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant
  • no domain-level missense hotspot literature identified for this residue.
Still missing
  • No domain-specific pathogenicity mapping includes position 185.
Sources
oncokb ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.334 (intermediate)
  • BayesDel -0.415 (benign-leaning)
  • SpliceAI max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 allele frequency = 0.0% (0/1
  • 113
  • 262 alleles).
Sources
gnomad_v4 ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 allele frequency = 0.0% (0/1
  • 113
  • 262 alleles).
Sources
gnomad_v4 ↗
BP1 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. Details ▾Hide ▴
Evidence considered
  • MYCN missense variants are an established mechanism of both FS1 (LoF) and MPS (GoF)
  • gene is not limited to truncating-variant disease.
Sources
pvs1_gene_context

Not assessed · 14 · no assessment recorded

PS2 No de novo data (confirmed or unconfirmed parentage) are available for this variant. Details ▾Hide ▴
Still missing
  • De novo status unknown
  • no family studies available.
PS4 No case-control or statistical enrichment data available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort studies involving this variant.
PM6 No de novo observation data (confirmed or unconfirmed parentage) are available for this variant. Details ▾Hide ▴
Still missing
  • De novo status unknown.
PP1 No co-segregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation studies available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for MYCN
  • no gnomAD missense constraint data available.
Still missing
  • No quantitative missense constraint data for MYCN.
PP4 No phenotype or family history data specific to this variant are available. The patient's clinical presentation has not been provided. Details ▾Hide ▴
Still missing
  • Proband phenotype not available for specificity assessment.
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no external classification available.
Still missing
  • No external laboratory or database classification.
Sources
clinvar ↗
BS2 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. Details ▾Hide ▴
Still missing
  • No population surveys or family studies identifying unaffected carriers.
BS3 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. Details ▾Hide ▴
Still missing
  • No experimental functional studies showing no deleterious effect.
BS4 No segregation data are available for this variant; lack of segregation with disease cannot be evaluated. Details ▾Hide ▴
Still missing
  • No family segregation data to evaluate.
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. Details ▾Hide ▴
Still missing
  • No trans/cis phase data available.
BP5 No data on this variant found in a case with an alternative molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data.
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar.
Still missing
  • No external benign classification.
Sources
clinvar ↗
PS5 No data on this variant observed in trans with a pathogenic variant for a recessive disorder. MYCN is an autosomal dominant disease gene. Details ▾Hide ▴
Still missing
  • No trans-phase data available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variant found in ClinVar.
Sources
pm5_candidates
BP7 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 criteria not applicable.

Identifiers

Gene
MYCN
Transcript
NM_005378.6
Coding (HGVS c.)
NM_005378.6:c.553G>A
Protein (HGVS p.)
NP_005369.2:p.(Glu185Lys)
GRCh38
chr2:15942617 G>A
GRCh37
chr2:16082739 G>A

Gene diagram

Every interpreted variant in MYCN, mapped onto the exon structure of NM_005378.6. Select a row to find it on the plot.

MYCNNM_005378.6
Fetching transcript structure from UCSC…
gnomAD v4.1 0 / 1,113,262 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,113,262 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -477 bp
0.000
SpliceAI acceptor gainat -213 bp
0.000
SpliceAI donor lossat +237 bp
0.000
SpliceAI donor gainat +1 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
0.334
BayesDel
-0.415

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • BayesDel -0.415 (benign prediction)
  • SpliceAI max delta 0.01 (no splice impact)
  • REVEL 0.334 (intermediate).
Sources
bayesdelspliceai ↗revel
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.334 (intermediate)
  • BayesDel -0.415 (benign-leaning)
  • SpliceAI max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis 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. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 criteria not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = -0.415487.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 0 / 1,113,262 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.