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MYCNc.1069C>TUncertain significance
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Variant interpretation report

MYCN c.1069C>T, p.(Arg357Cys)

NM_005378.6:c.1069C>T NP_005369.2:p.(Arg357Cys) 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

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

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; 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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
3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99807954, n = 3 times).

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 · 20 not met · 1 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): 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).

Met · 2

PM2 SupportingExtremely 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. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 3/1
  • 614
  • 110 alleles (AF=1.86e-06
  • MAF=0.00019%)
  • gnomAD v2.1: absent
  • gnomAD-Canada: absent.
Sources
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.26
  • BayesDel -0.326
  • SpliceAI max delta 0.00.
Sources
revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No established pathogenic missense variant at codon 357 has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar absent
  • PM5 candidate search returned no same-codon pathogenic comparators.
Sources
clinvar ↗pm5_candidates
PS2 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar or literature.
Still missing
  • Parental genotype data unavailable.
PS3 No variant-specific functional studies identified. REVEL (0.26) and BayesDel (-0.326) are computational predictions, not experimental functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB: no variant-specific reviewed functional evidence
  • REVEL 0.26
  • BayesDel -0.326.
Still missing
  • No experimental functional data for p.Arg357Cys.
Sources
revelbayesdeloncokb ↗
PS4 No case-control or prevalence data available; variant absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no case counts available.
Still missing
  • No affected vs. control comparison data.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no statistically significant hotspot at residue 357.
Still missing
  • No domain-specific functional characterization for Arg357.
PM5 No pathogenic missense variant at codon 357 identified; PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found no same-residue pathogenic comparators
  • ClinVar absent.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo data available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in any source.
Still missing
  • Parental genotype data unavailable.
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data identified.
Still missing
  • Family segregation data unavailable.
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.26
  • BayesDel -0.326
  • SpliceAI max delta 0.00
  • HCI prior not available.
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data provided for assessment. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype data available.
Still missing
  • Patient phenotype information unavailable.
PP5 Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no ClinVar submissions exist.
Sources
clinvar ↗
BA1 gnomAD v4.1 allele frequency is 0.00019%, far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00019%
  • well below 1%.
Sources
gnomad_v4 ↗
BS1 gnomAD v4.1 allele frequency is 0.00019%, below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.00019%
  • below 0.3%.
Sources
gnomad_v4 ↗
BS2 No data on observation in healthy adults; MYCN-associated conditions are fully penetrant autosomal dominant disorders. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available.
Still missing
  • Healthy adult carrier data unavailable.
BS3 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. Details ▾Hide ▴
Evidence considered
  • No experimental functional studies available
  • OncoKB reports unknown oncogenic effect.
Still missing
  • No experimental functional data.
Sources
revelbayesdeloncokb ↗
BS4 No non-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • Family segregation data unavailable.
BP1 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. Details ▾Hide ▴
Evidence considered
  • MYCN has documented pathogenic missense variants in germline disease
  • BP1 cannot be applied.
BP2 No data on observation in trans with a pathogenic variant; MYCN disorders are autosomal dominant. Details ▾Hide ▴
Evidence considered
  • No trans configuration data available.
BP5 No alternate molecular basis for disease identified; no case data available. Details ▾Hide ▴
Evidence considered
  • No data on alternate molecular cause.
Still missing
  • Clinical case data unavailable.
BP6 Variant is absent from ClinVar; no reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classifications exist.
Sources
clinvar ↗

Not assessed · 1 · no assessment recorded

PP2 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. Details ▾Hide ▴
Evidence considered
  • No gnomAD missense constraint metrics (z-score
  • o/e) available in case evidence.
Still missing
  • gnomAD missense constraint data needed for MYCN.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Arg357Cys) does not meet PVS1 null-variant criteria; not a nonsense, frameshift, or canonical ±1,2 splice site variant. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • generic PVS1 framework requires null-variant type.
Sources
pvs1_generic_framework ↗
BP7 N/AMissense variant (p.Arg357Cys); BP7 applies only to synonymous or intronic variants without predicted splice effect. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • BP7 not applicable.
PS5 N/ANot a standard ACMG/AMP 2015 criterion; no applicable evidence framework for this code. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MYCN
Transcript
NM_005378.6
Coding (HGVS c.)
NM_005378.6:c.1069C>T
Protein (HGVS p.)
NP_005369.2:p.(Arg357Cys)
GRCh38
chr2:15945771 C>T
GRCh37
chr2:16085893 C>T
COSMIC
COSV99807954

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 3 / 1,614,110 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,614,110 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,180,022 2.5e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85861e-06; MAF= 0.00019%, 3/1614110 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54233e-06; MAF= 0.00025%, 3/1180022 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -84 bp
0.000
SpliceAI acceptor gainat -292 bp
0.000
SpliceAI donor lossat +164 bp
0.000
SpliceAI donor gainat -169 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.260
BayesDel
-0.326

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.26
  • BayesDel -0.326
  • SpliceAI max delta 0.00.
Sources
revelbayesdelspliceai ↗
PP3 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). Details ▾Hide ▴
Evidence considered
  • REVEL 0.26
  • BayesDel -0.326
  • SpliceAI max delta 0.00
  • HCI prior not available.
Sources
revelbayesdelspliceai ↗
BP7 N/AMissense variant (p.Arg357Cys); BP7 applies only to synonymous or intronic variants without predicted splice effect. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.26. BayesDel score = -0.326084.

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 3 / 1,614,110 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 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= 1.85861e-06; MAF= 0.00019%, 3/1614110 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54233e-06; MAF= 0.00025%, 3/1180022 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

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 = 0.00). REVEL score = 0.26. BayesDel score = -0.326084.

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 previously been reported in somatic cancers (COSMIC; COSV99807954, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.