About MYCN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYCN c.865_867del, p.(Ser289del)
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
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases. In gnomAD v2.1 the allele frequency is 0.00637% (2/31,376 alleles, 0 homozygotes) and in gnomAD v4.1 the allele frequency is 0.00043% (7/1,613,892 alleles, 0 homozygotes). Both are well below the 0.1% threshold, consistent with a rare variant absent from controls at appreciable frequency.
PM4Moderate
PM4 · moderate
NM_005378.6:c.865_867del results in an in-frame deletion of a single amino acid (p.Ser289del) within MYCN exon 3. This changes the protein length in a non-repeat region of a gene where loss of function is an established disease mechanism for Feingold syndrome type 1.
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: PM2 supporting, PM4 moderate; 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
7 / 1,613,892 alleles
gnomAD v4.1: 7 / 1,613,892 alleles. Recorded AF 4.33734e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.3743e-05; MAF= 0.00637%, 2/31376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000129685; MAF= 0.01297%, 2/15422 alleles, homozygotes = 0); grpmax FAF= 2.241e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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 · 7 not met · 0 not assessed · 20 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005378.6:c.865_867del (p.Ser289del) is an in-frame deletion of a single amino acid in exon 3 of MYCN, a gene in which loss-of-function variants cause autosomal dominant Feingold syndrome type 1.
This variant does not meet PVS1 criteria as it is not a null variant (nonsense, frameshift, or canonical splice site).
The variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00637% (2/31,376 alleles) and gnomAD v4.1 AF = 0.00043% (7/1,613,892 alleles), with no homozygotes observed, meeting PM2 at supporting strength.
The in-frame deletion changes protein length (p.Ser289del) in a non-repeat region of MYCN, meeting PM4 at moderate strength.
No variant-specific functional studies, segregation data, de novo observations, or case-control evidence are available. ClinVar reports a single classification of uncertain significance.
Computational evidence is limited: SpliceAI predicts no splicing impact (max delta = 0.04), and REVEL/BayesDel are not applicable to deletions. PP3 and BP4 are not met.
Overall classification: Uncertain Significance. One moderate criterion (PM4) and one supporting criterion (PM2) are met, which is insufficient to reach likely pathogenic or likely benign under the ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases. In gnomAD v2.1 the allele frequency is 0.00637% (2/31,376 alleles, 0 homozygotes) and in gnomAD v4.1 the allele frequency is 0.00043% (7/1,613,892 alleles, 0 homozygotes). Both are well below the 0.1% threshold, consistent with a rare variant absent from controls at appreciable frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=6.37e-05 (0.00637%)
- 2/31
- 376 alleles
- 0 homozygotes
- gnomAD v4.1: AF=4.34e-06 (0.00043%)
- 7/1
- 613
- 892 alleles
- Highest subpopulation AF (v2.1 NFE): 0.013%
- still well below 0.1% threshold
Sources
PM4 ModerateNM_005378.6:c.865_867del results in an in-frame deletion of a single amino acid (p.Ser289del) within MYCN exon 3. This changes the protein length in a non-repeat region of a gene where loss of function is an established disease mechanism for Feingold syndrome type 1. Details ▾Hide ▴
Evidence considered
- In-frame single amino acid deletion (p.Ser289del) resulting in protein length change
- No evidence that position 289 lies within a repetitive region
- MYCN LoF is an established mechanism for Feingold syndrome type 1 (autosomal dominant)
Sources
pvs1_gene_context
Not met · 7 · evaluated, threshold not reached
PVS1 NM_005378.6:c.865_867del is an in-frame deletion of a single amino acid (p.Ser289del) and does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Although MYCN loss of function is a known disease mechanism for Feingold syndrome type 1, this variant type does not meet PVS1 criteria. Details ▾Hide ▴
Evidence considered
- In-frame single amino acid deletion (p.Ser289del) in exon 3 of MYCN
- Variant bucket: 'other' — not a null variant
- Gene-level PVS1 gate: eligible (LoF mechanism supported for Feingold syndrome)
- Variant-level assessment: apply_generic_pvs1_framework=false
- does not meet null variant criteria per PMC6185798
Sources
PS4 No case-control or statistical evidence supports pathogenicity. The variant has a single ClinVar submitter with a classification of uncertain significance. No published patient case reports or cohort studies describe this variant in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided
- single submitter
Still missing
- No published case observations or case-control studies for this variant
Sources
PM1 The variant does not lie within a statistically significant mutational hotspot or a well-established critical functional domain where all missense variation is known to be pathogenic. Residue-level hotspot analysis was negative. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- exact variant not listed as a hotspot
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL and BayesDel are not applicable to non-SNV variants (deletion). SpliceAI predicts no significant splice impact (max delta score = 0.04). No HCI prior score is available for MYCN. In the absence of convergent in silico evidence, PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.04 (no significant splice impact predicted)
- REVEL: not applicable (deletion
- not SNV)
- BayesDel: not applicable (deletion
- HCI prior: not supported for MYCN
Still missing
- No in silico missense/deletion-specific predictors available for in-frame deletions
Sources
BA1 The allele frequency is far below the 1% threshold for BA1. In gnomAD v4.1 the overall AF is 0.00043% (7/1,613,892 alleles), and in v2.1 it is 0.00637% (2/31,376 alleles). The variant is not common enough in any population to meet the stand-alone benign criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00637% (far below 1%)
- gnomAD v4.1: AF=0.00043% (far below 1%)
Sources
BS1 The allele frequency is below the 0.3% threshold. Highest subpopulation AF in gnomAD v2.1 (NFE) is 0.013% and in gnomAD v4.1 (Remaining) is 0.0064%, both well below 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: max subpopulation AF = 0.013% (NFE
- below 0.3%)
- gnomAD v4.1: max subpopulation AF = 0.0064% (Remaining
Sources
BP4 Insufficient multiple lines of computational evidence support a benign effect. SpliceAI alone (max delta = 0.04) suggests no splicing impact, but REVEL and BayesDel are not applicable to deletions. A single line of in silico evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.04 (no significant splice impact predicted)
- REVEL/BayesDel: not applicable to non-SNV variants
Still missing
- No in silico tools specifically designed to predict the functional impact of in-frame deletions
Sources
Not applicable · 20· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change at the same position has been previously classified as pathogenic. This is an in-frame deletion, not a nucleotide substitution with a known pathogenic alternative change at the same residue. Details ▾Hide ▴
No further detail was recorded.
PS2 N/ANo de novo occurrence data (paternity and maternity confirmed or unconfirmed) has been reported for this variant in any published study or database. Details ▾Hide ▴
No further detail was recorded.
PS3 N/ANo variant-specific functional studies have been identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional evidence. No publications report functional assays for NM_005378.6:c.865_867del. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
Sources
PM3 N/ASkipped per adjudication directive. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously established. This variant is an in-frame deletion (p.Ser289del), not a missense substitution. No same-residue comparator candidates were identified. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: not applicable — variant is a deletion
- not a missense substitution
Sources
pm5_candidates
PM6 N/ANo de novo occurrence has been reported for this variant. No parent-of-origin testing data are available. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo segregation data have been reported for this variant in any affected family members. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This variant is an in-frame deletion, not a missense substitution. Additionally, no HCI prior gene-level constraint data are available for MYCN. Details ▾Hide ▴
No further detail was recorded.
PP4 N/ANo patient phenotype or family history data are available for this variant. PP4 requires the variant to be observed in a patient with a phenotype highly specific for the gene. Details ▾Hide ▴
No further detail was recorded.
PP5 N/ANo reputable source has recently classified this variant as pathogenic. ClinVar reports a single submission of uncertain significance. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo observation of this variant in a homozygous or hemizygous state in healthy adults has been reported. MYCN-related Feingold syndrome is autosomal dominant with haploinsufficiency; the BS2 criterion is not applicable without specific healthy control data. Details ▾Hide ▴
No further detail was recorded.
BS3 N/ANo well-established functional studies demonstrate that this variant has no deleterious effect on protein function or splicing. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo segregation data are available to assess lack of co-segregation with disease in affected family members. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary known disease mechanism. This is an in-frame deletion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo observation of this variant in trans with a known pathogenic variant in MYCN has been reported. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. There is no evidence that position 289 of MYCN lies within a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source has recently classified this variant as benign. ClinVar reports a single uncertain significance submission. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. This variant is an in-frame deletion, not a synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
PS5 N/ANo reputable source has recently classified this variant as pathogenic. ClinVar reports uncertain significance from a single submitter. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MYCN
- Transcript
- NM_005378.6
- Coding (HGVS c.)
- NM_005378.6:c.865_867del
- Protein (HGVS p.)
- NP_005369.2:p.(Ser289del)
- GRCh38
- chr2:15945560 TTCC>T
- GRCh37
- chr2:16085682 TTCC>T
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…
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
7 / 1,613,892 alleles
AF 4.34e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
2 / 31,376 alleles
AF 6.37e-05 · 0 homozygotes · FAF 2.24e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.3e-06 · 7 / 1,613,892 alleles · 0 hom · FAF 6.8e-07
| Remaining individuals4 / 62,488 | 6.4e-05 |
| European (non-Finnish)3 / 1,179,982 | 2.5e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 6.4e-05 · 2 / 31,376 alleles · 0 hom · FAF 2.2e-05
| European (non-Finnish)2 / 15,422 | 0.00013 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.33734e-06; MAF= 0.00043%, 7/1613892 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40123e-05; MAF= 0.00640%, 4/62488 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.3743e-05; MAF= 0.00637%, 2/31376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000129685; MAF= 0.01297%, 2/15422 alleles, homozygotes = 0); grpmax FAF= 2.241e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL and BayesDel are not applicable to non-SNV variants (deletion). SpliceAI predicts no significant splice impact (max delta score = 0.04). No HCI prior score is available for MYCN. In the absence of convergent in silico evidence, PP3 is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.04 (no significant splice impact predicted)
- REVEL: not applicable (deletion
- not SNV)
- BayesDel: not applicable (deletion
- HCI prior: not supported for MYCN
Still missing
- No in silico missense/deletion-specific predictors available for in-frame deletions
Sources
BP4 Insufficient multiple lines of computational evidence support a benign effect. SpliceAI alone (max delta = 0.04) suggests no splicing impact, but REVEL and BayesDel are not applicable to deletions. A single line of in silico evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.04 (no significant splice impact predicted)
- REVEL/BayesDel: not applicable to non-SNV variants
Still missing
- No in silico tools specifically designed to predict the functional impact of in-frame deletions
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. This variant is an in-frame deletion, not a synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and AMP. This methodology paper describes the ACMG/AMP variant classification framework and does not reference any specific variants, including NM_005378.6:c.865_867del.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
7 / 1,613,892 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
2 Uncertain significance
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_005378.6%3Ac.865_867delTCC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-16085682-TTCC-T?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-15945560-TTCC-T?dataset=…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-15945560-TTCC-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005378.6%3Ac.865_…
- OncoKB ↗www.oncokb.org/gene/MYCN/S289del
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MYCN+c.865_867del
- 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
This variant is present in gnomAD v4.1 (AF= 4.33734e-06; MAF= 0.00043%, 7/1613892 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 6.40123e-05; MAF= 0.00640%, 4/62488 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.3743e-05; MAF= 0.00637%, 2/31376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000129685; MAF= 0.01297%, 2/15422 alleles, homozygotes = 0); grpmax FAF= 2.241e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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.