About MYCN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYCN c.1340T>C, p.(Leu447Ser)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
Residue Leu447 is located within the C-terminal leucine zipper domain of MYCN (approximately residues 440-464), a well-established critical functional domain required for protein dimerization and DNA binding. The variant is absent from gnomAD, consistent with a lack of benign variation in this domain.
PM2Supporting
PM2 · supporting
NM_005378.5:c.1340T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% population allele frequency under generic ACMG/AMP rules.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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: PM1 moderate, PM2 supporting; combination = 1 moderate + 1 supporting, 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 5 not met · 17 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005378.5:c.1340T>C (p.Leu447Ser) is a missense variant in MYCN, located within the C-terminal leucine zipper domain critical for protein dimerization and DNA binding. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
PM1 (moderate) is met: residue Leu447 lies within the MYCN leucine zipper domain, a well-established critical functional domain. The variant is absent from population databases, consistent with a lack of benign variation in this region.
PM2 (supporting) is met: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency <0.1%).
PVS1 is not applicable: the variant is a missense substitution and does not qualify as a predicted null variant under PMC6185798.
PP3 is not met: in silico predictors are conflicting (REVEL 0.767 damaging, BayesDel 0.164 neutral). BP4 is also not met for the same reason.
BP1 is not met: missense variants in MYCN are a known disease mechanism for Feingold syndrome type 1 and megalencephaly-polydactyly syndrome.
With one moderate criterion (PM1) and one supporting criterion (PM2), this combination does not reach the Likely Pathogenic threshold under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 ModerateResidue Leu447 is located within the C-terminal leucine zipper domain of MYCN (approximately residues 440-464), a well-established critical functional domain required for protein dimerization and DNA binding. The variant is absent from gnomAD, consistent with a lack of benign variation in this domain. Details ▾Hide ▴
Evidence considered
- Leu447 resides in the leucine zipper domain
- critical for MYCN dimerization and DNA binding. Variant absent from all gnomAD populations.
Still missing
- Formal domain boundary annotation from ClinGen or a VCEP would strengthen this call. Cancerhotspots.org does not flag this residue as statistically significant.
Sources
PM2 SupportingNM_005378.5:c.1340T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% population allele frequency under generic ACMG/AMP rules. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- gnomAD v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes). Allele count = 0 across all population databases.
Sources
Not met · 5 · evaluated, threshold not reached
PP3 In silico predictions are conflicting: REVEL score of 0.767 falls in the damaging range (≥0.5), but the BayesDel score of 0.164 is in the neutral/benign range. SpliceAI predicts no splice impact (max delta 0.01). Multiple lines of computational evidence do not consistently support a deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.767 (damaging range)
- BayesDel: 0.164 (benign/neutral range)
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
BA1 NM_005378.5:c.1340T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which does not meet the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations. Allele frequency = 0%.
Sources
BS1 NM_005378.5:c.1340T>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which does not meet the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations. Allele frequency = 0%.
Sources
BP1 Missense variants in MYCN are a known disease mechanism. MYCN missense variants have been reported to cause Feingold syndrome type 1 (via loss-of-function missense) and megalencephaly-polydactyly syndrome (via gain-of-function missense). MYCN is not a gene for which primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- MYCN missense variant c.454G>A (p.Ala152Thr) reported in Feingold syndrome type 1
- missense variants are established as causative for both FS1 and MPS.
BP4 The REVEL score of 0.767 falls in the damaging range, and SpliceAI shows no splice impact (max delta 0.01). The BayesDel score of 0.164 is in the neutral range, but multiple lines of computational evidence do not consistently suggest a benign effect. BP4 requires multiple lines of in silico evidence supporting no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.767 (damaging)
- BayesDel: 0.164 (neutral)
- SpliceAI: 0.01 (no splice impact). At least one predictor (REVEL) is in the damaging range.
Sources
Not assessed · 17 · no assessment recorded
PS1 No known pathogenic variant at the same amino acid residue (Leu447) with a different nucleotide change has been identified. The variant is absent from ClinVar, and no comparator data are available. Details ▾Hide ▴
Evidence considered
- No ClinVar entries at this residue
- no pathogenic comparators available for PS1 assessment.
Still missing
- Requires identification of a pathogenic missense variant at Leu447 with a different nucleotide change.
Sources
PS2 No de novo occurrence data with confirmed paternity and maternity are available for this variant. Details ▾Hide ▴
Still missing
- Requires a de novo observation with confirmed parentage for this variant.
PS3 No well-established functional studies demonstrating a damaging effect have been identified for NM_005378.5:c.1340T>C (p.Leu447Ser). OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data curated.
Still missing
- Requires variant-specific functional assay data (e.g.
- transcriptional activity
- protein stability
- dimerization) demonstrating a damaging effect.
Sources
PS4 No case-control or cohort studies reporting this variant in affected individuals have been identified. The variant is absent from ClinVar and has not been reported in the literature. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no literature reports identified.
Still missing
- Requires case-control or cohort data comparing prevalence of this variant in affected versus unaffected individuals.
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Leu447) with a different amino acid change has been identified. PM5 candidate harvesting yielded zero same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- Zero same-residue pathogenic comparator variants identified at Leu447 in ClinVar.
Still missing
- Requires identification of a pathogenic variant at Leu447 with a different alternate amino acid.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (without confirmation of paternity and maternity) has been identified for this variant. Details ▾Hide ▴
Still missing
- Requires a de novo observation of this variant in an affected individual.
PP1 No co-segregation data are available for NM_005378.5:c.1340T>C. The variant has not been reported in any families. Details ▾Hide ▴
Still missing
- Requires co-segregation data in affected family members.
PP2 Gene-level constraint data are not available for MYCN (HCI prior not found), and gnomAD missense constraint metrics (Z-score, o/e) were not retrieved. The rate of benign missense variation in MYCN cannot be assessed. Details ▾Hide ▴
Evidence considered
- HCI prior not found for MYCN
- no constraint data available for PP2 assessment.
Still missing
- Requires gene-level constraint metrics (e.g.
- gnomAD missense Z-score
- o/e ratio) demonstrating a low rate of benign missense variation.
PP4 No patient phenotype or family history data are available for this variant. No clinical cases have been reported. Details ▾Hide ▴
Still missing
- Requires patient phenotype data consistent with a MYCN-related disorder (e.g.
- Feingold syndrome type 1).
PP5 This variant has not been reported as pathogenic by a reputable source. It is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has classified this variant as pathogenic.
Still missing
- Requires a reputable source classification of pathogenicity.
Sources
BS2 No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- Requires data on observation in healthy adult individuals for a disorder with full penetrance expected at an early age.
BS3 No well-established functional studies demonstrating no damaging effect have been identified for this variant. Details ▾Hide ▴
Still missing
- Requires functional assay data demonstrating no damaging effect on protein function.
BS4 No segregation data are available to assess lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- Requires segregation data in affected families.
BP2 No evidence of observation in trans with a pathogenic variant is available. MYCN-related disorders are autosomal dominant. Details ▾Hide ▴
Still missing
- Observation in trans with a pathogenic variant is unlikely in an autosomal dominant disorder but could be assessed if data become available.
BP5 No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- Requires identification of the variant in a case with a confirmed alternate molecular cause of the phenotype.
BP6 This variant has not been reported as benign by a reputable source. It is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has classified this variant as benign.
Still missing
- Requires a reputable source classification of benignity.
Sources
PS5 This variant has not been reported as pathogenic by a reputable source. It is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no submitter classifications available.
Still missing
- Requires a reputable source (e.g.
- clinical diagnostic laboratory) reporting this variant as pathogenic.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_005378.5:c.1340T>C is a missense variant (p.Leu447Ser) and does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per pvs1_variant_assessment.json, apply_generic_pvs1_framework is false; PVS1 is reserved for predicted null variants. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu447Ser)
- variant_bucket=other
- not eligible for PVS1 under PMC6185798.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders requiring detection in trans with a pathogenic variant. MYCN-related disorders (Feingold syndrome type 1, megalencephaly-polydactyly syndrome) are autosomal dominant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 is reserved for protein length-altering variants (in-frame deletions/insertions, stop-loss). NM_005378.5:c.1340T>C is a missense substitution that does not alter protein length. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 is reserved for in-frame deletions/insertions in a repetitive region. NM_005378.5:c.1340T>C is a single-nucleotide substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is reserved for synonymous variants with no predicted splice impact. NM_005378.5:c.1340T>C is a missense variant (p.Leu447Ser). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MYCN
- Transcript
- NM_005378.5
- Coding (HGVS c.)
- NM_005378.5:c.1340T>C
- Protein (HGVS p.)
- NP_005369.2:p.(Leu447Ser)
- GRCh38
- chr2:15946042 T>C
- GRCh37
- chr2:16086164 T>C
Gene diagram
Every interpreted variant in MYCN, mapped onto the exon structure of NM_005378.5. Select a row to find it on the plot.
MYCNNM_005378.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MYCN
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.767
- BayesDel
- 0.164
How the predictions were used
PP3 In silico predictions are conflicting: REVEL score of 0.767 falls in the damaging range (≥0.5), but the BayesDel score of 0.164 is in the neutral/benign range. SpliceAI predicts no splice impact (max delta 0.01). Multiple lines of computational evidence do not consistently support a deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.767 (damaging range)
- BayesDel: 0.164 (benign/neutral range)
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
BP4 The REVEL score of 0.767 falls in the damaging range, and SpliceAI shows no splice impact (max delta 0.01). The BayesDel score of 0.164 is in the neutral range, but multiple lines of computational evidence do not consistently suggest a benign effect. BP4 requires multiple lines of in silico evidence supporting no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.767 (damaging)
- BayesDel: 0.164 (neutral)
- SpliceAI: 0.01 (no splice impact). At least one predictor (REVEL) is in the damaging range.
Sources
BP7 N/ABP7 is reserved for synonymous variants with no predicted splice impact. NM_005378.5:c.1340T>C is a missense variant (p.Leu447Ser). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.767. BayesDel score = 0.163771.
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
Captured gnomAD v4.1 source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005378.5%3Ac.1340T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-16086164-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-15946042-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-15946042-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005378.5%3Ac.1340…
- OncoKB ↗www.oncokb.org/gene/MYCN/L447S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MYCN+c.1340T%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
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 = 0.767. BayesDel score = 0.163771.
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.