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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYCN is a transcription factor that controls the expression of genes involved in cell growth, division, survival, and metabolism. It is normally active mainly during embryonic development and is largely restricted to cells of the nervous system and a few other tissues. Amplification of MYCN drives cancer, most notably neuroblastoma, and is also seen in medulloblastoma, glioblastoma, and other solid tumors such as breast and small cell lung cancers.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with zero alleles across 1,599,516.
Met (supporting): REVEL 0.216 meets the <=0.290 benign-supporting threshold, and SpliceAI max delta 0.003 predicts no splice impact.
VUS: only PM2 (supporting, absent from gnomAD) and BP4 (supporting, REVEL 0.216) are met; opposing supporting criteria satisfy no ACMG/AMP 2015 combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 0 / 1,599,516 alleles. Recorded AF 0. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.216. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not 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.
This variant has previously been reported in somatic cancers (COSMIC; COSV107256617, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 18 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No functional assay evidence (published or VCEP-referenced) exists for NM_005378.5:c.368G>T in this case bundle; both PS3 and BS3 are not_assessed rather than not_met/not_applicable because absence of data, not evidence against applicability, is the driver.
MYCN has no ClinGen VCEP specification in this case (cspec.found=false), so generic ACMG/AMP was the only available framework, and even under generic ACMG no qualifying assay data were located to apply.
MYCN has no ClinGen VCEP-specific PP3/BP4 lookup materials in this case; generic ACMG/AMP in-silico evidence rules were applied.
Variant is missense (p.Arg123Leu); REVEL (0.216) and SpliceAI (max delta 0.003) both indicate a non-damaging, non-splice-disrupting prediction, supporting BP4 at supporting strength and precluding PP3.
BayesDel score was available but excluded from PP3/BP4 determination because no verified published calibration threshold could be named for it.
BP7 is not applicable because this is a missense variant, not synonymous.
No applicable MYCN ClinGen CSPEC/VCEP framework was available in the case bundle; generic ACMG/AMP 2015 population criteria were therefore used.
Population data support PM2 at supporting strength and do not support BA1, BS1, or BS2.
No criteria match.
PM2 is met at supporting strength. NM_005378.5:c.368G>T (NP_005369.2:p.Arg123Leu) is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and has zero observed alleles in gnomAD v4.1 across 1,599,516 alleles, including zero homozygotes and zero alleles in each listed ancestry group.
Generic ACMG/AMP 2015 PM2: variant absent from or extremely rare in population databases; applied as supporting evidence because no applicable MYCN VCEP specification was retrieved.
No governing VCEP/gene-specific PP3/BP4 lookup material is available for MYCN, so generic ACMG in-silico evidence applies. REVEL score is 0.216 for the missense variant p.(Arg123Leu), which falls at/below the ClinGen SVI-calibrated benign-supporting REVEL threshold (<=0.290) from Pejaver et al. 2022 (PMID 36413997), supporting a benign computational prediction at supporting strength. Independently, SpliceAI predicts no meaningful splice impact (max delta score = 0.003), consistent with no disruption of normal splicing. Both computational lines converge on a benign/non-damaging prediction; per instructions this convergent evidence is applied as a single BP4 code at supporting strength rather than stacked strength. BayesDel is excluded from this determination (no verified published threshold available to this pipeline).
generic_acmg
No governing VCEP/gene-specific PP3/BP4 lookup material is available for MYCN in this case (cspec.found=false; vcep_materials empty), so generic ACMG in-silico evidence applies. NM_005378.5:c.368G>T is a missense variant (NP_005369.2:p.(Arg123Leu)). REVEL score is 0.216, well below the ClinGen SVI-calibrated pathogenic-supporting threshold (>=0.644), so it does not support a damaging prediction. SpliceAI predicts no meaningful splice impact (max delta score = 0.003, far below the 0.2 SpliceAI threshold used to flag potential splicing effects), so the splice-impact path also does not support PP3. BayesDel score (-0.349224) is present in prefetch data but is excluded from consideration: no verified published calibration/threshold for BayesDel is available to this pipeline, so it is treated as not_available for PP3/BP4 regardless of the raw score. No convergent computational evidence supports a deleterious effect on protein function or splicing.
generic_acmg
BA1 is not met. The variant has total allele frequency 0 in gnomAD v4.1 (0/1,599,516 alleles), with no observed homozygotes; this is far below the generic ACMG/AMP stand-alone benign threshold of greater than 5%.
Generic ACMG/AMP 2015 BA1: allele frequency greater than 5% supports stand-alone benign classification; no applicable MYCN VCEP specification was retrieved.
BS1 is not met. The variant is absent from the available population datasets rather than present at a frequency greater than expected for a pathogenic MYCN variant. No population frequency, disease prevalence, penetrance, or genetic-model information supports a BS1 threshold artifact.
Generic ACMG/AMP 2015 BS1: allele frequency is greater than expected for the disorder; absence of the variant does not satisfy BS1.
BS2 is not met. No healthy individual carrying the variant, and no homozygous healthy individual, is reported in the reviewed population datasets. The available data therefore do not provide the observation required for this benign criterion.
Generic ACMG/AMP 2015 BS2: observation of the variant in healthy adults, or in healthy individuals homozygous for a recessive disorder, can support benign evidence; no such observation is available here.
PS1 could not be assessed because its agent did not produce valid output.
No case-specific parental testing, trio analysis, or other documented evidence establishing that NM_005378.5:c.368G>T (p.Arg123Leu) is de novo was found. PS2 cannot be assessed without confirmed maternity and paternity and verified absence of the variant in both biological parents.
Generic ACMG/AMP PS2: apply only when the variant is shown to be de novo in a patient with the disease and confirmed maternity and paternity; no applicable MYCN-specific specification was available.
No functional/biochemical assay data (e.g., MYCN transactivation, proliferation, degron/phosphodegron, or transformation assays) for NM_005378.5:c.368G>T (p.Arg123Leu) were identified in the evidence bundle. No ClinGen VCEP specification exists for MYCN (cspec.found=false; framework_mode=generic_acmg), so no gene-specific functional assay calibration is available either. OncoKB was queried and explicitly returned no variant-specific reviewed functional evidence, only general gene-level context that MYCN is altered by amplification/overexpression in cancer. The literature pass found zero PMIDs for this variant. There is no basis to assess PS3.
No statistically interpretable germline case-control enrichment, affected-case series, or exact-variant comparison with controls is available for NM_005378.5:c.368G>T (NP_005369.2:p.Arg123Leu). The one somatic COSMIC record is not germline case-control evidence and cannot establish PS4.
PS4 requires a statistically significant increased frequency of the variant in affected individuals or an affected cohort compared with appropriate controls; a somatic-only record is insufficient.
PM1 could not be assessed because its agent did not produce valid output.
PM3 cannot be assessed because the consolidated case-evidence bundle contains no affected-proband observations, familial genotype data, phase information, or documented pathogenic variant in trans for NM_005378.5:c.368G>T (MYCN p.Arg123Leu). The absence of a ClinVar record and population-frequency data does not establish PM3.
Generic ACMG/AMP PM3: pathogenic variants in trans with the variant under evaluation in an affected individual, with strength determined by the number and quality of observations.
PM5 could not be assessed because its agent did not produce valid output.
No case-specific evidence of a presumed de novo occurrence was found. In the absence of documented parental testing or a reliable de novo report with unconfirmed parentage, PM6 cannot be applied.
Generic ACMG/AMP PM6: apply only for a presumed de novo variant when maternity and/or paternity has not been confirmed; no applicable MYCN-specific specification was available.
No affected relatives carrying the variant, informative meioses, or family segregation data were documented. Therefore, cosegregation cannot be evaluated and PP1 is not assessed.
Generic ACMG/AMP PP1: apply when a variant cosegregates with disease in affected family members; strength may depend on the number of informative meioses, but no segregation data are available and no MYCN-specific specification was retrieved.
PP2 could not be assessed because its agent did not produce valid output.
The consolidated case-evidence bundle does not provide the patient's phenotype, the suspected MYCN-related disorder, or a phenotype-specific likelihood assessment. Gene-level MYCN context and an unreviewed OncoKB summary do not establish a highly specific phenotype for PP4.
PP4 requires a patient's phenotype or family history that is highly specific for a disease with a single-gene etiology; unavailable or nonspecific phenotype information is insufficient.
The exact variant has no ClinVar result in the case-evidence bundle. Therefore, no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available to trigger PP5.
Apply PP5 only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions are excluded.
No functional assay data showing normal/wild-type-like activity for NM_005378.5:c.368G>T (p.Arg123Leu) were identified. As with PS3, no MYCN VCEP specification exists to define validated assays or BS3 calibration, OncoKB found no variant-specific reviewed functional evidence, and the literature pass identified zero PMIDs referencing this variant. There is no basis to assess BS3.
No unaffected relatives were tested or documented as carrying or not carrying the variant, and no family phenotype/genotype data permit evaluation of non-segregation. BS4 cannot be assessed.
Generic ACMG/AMP BS4: apply when a variant does not segregate with disease in affected members of a family; this requires informative family data, which are absent, and no MYCN-specific specification was retrieved.
BP1 could not be assessed because its agent did not produce valid output.
BP2 cannot be assessed because the consolidated case-evidence bundle contains no genotype-level co-occurrence or phase data showing NM_005378.5:c.368G>T (MYCN p.Arg123Leu) in trans with a benign variant or in cis with a pathogenic variant. The absence of a ClinVar record and population-frequency data does not establish BP2.
Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant or in cis with a pathogenic variant, when the disease mechanism and phase context support a benign interpretation of the variant under evaluation.
No confirmed alternate molecular etiology explaining the patient's phenotype is provided. The single somatic COSMIC occurrence is unrelated to establishing an alternate germline diagnosis and cannot establish BP5.
BP5 requires an alternate molecular basis that explains the phenotype, such as an established pathogenic variant at another locus; an unrelated somatic occurrence is insufficient.
The exact variant has no ClinVar result in the case-evidence bundle. Therefore, no exact-variant ClinVar expert-panel Benign or Likely benign classification is available to trigger BP6.
Apply BP6 only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary submissions, aggregate labels, and non-expert assertions are excluded.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005378.5:c.368G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Arg123Leu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_005378.5:c.368G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Arg123Leu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005378.5:c.368G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Arg123Leu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005378.5:c.368G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Arg123Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in MYCN, mapped onto the exon structure of NM_005378.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1599516 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74962 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
No governing VCEP/gene-specific PP3/BP4 lookup material is available for MYCN, so generic ACMG in-silico evidence applies. REVEL score is 0.216 for the missense variant p.(Arg123Leu), which falls at/below the ClinGen SVI-calibrated benign-supporting REVEL threshold (<=0.290) from Pejaver et al. 2022 (PMID 36413997), supporting a benign computational prediction at supporting strength. Independently, SpliceAI predicts no meaningful splice impact (max delta score = 0.003), consistent with no disruption of normal splicing. Both computational lines converge on a benign/non-damaging prediction; per instructions this convergent evidence is applied as a single BP4 code at supporting strength rather than stacked strength. BayesDel is excluded from this determination (no verified published threshold available to this pipeline).
generic_acmg
No governing VCEP/gene-specific PP3/BP4 lookup material is available for MYCN in this case (cspec.found=false; vcep_materials empty), so generic ACMG in-silico evidence applies. NM_005378.5:c.368G>T is a missense variant (NP_005369.2:p.(Arg123Leu)). REVEL score is 0.216, well below the ClinGen SVI-calibrated pathogenic-supporting threshold (>=0.644), so it does not support a damaging prediction. SpliceAI predicts no meaningful splice impact (max delta score = 0.003, far below the 0.2 SpliceAI threshold used to flag potential splicing effects), so the splice-impact path also does not support PP3. BayesDel score (-0.349224) is present in prefetch data but is excluded from consideration: no verified published calibration/threshold for BayesDel is available to this pipeline, so it is treated as not_available for PP3/BP4 regardless of the raw score. No convergent computational evidence supports a deleterious effect on protein function or splicing.
generic_acmg
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_005378.5:c.368G>T in MYCN is a missense substitution predicted to produce NP_005369.2:p.(Arg123Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.216. BayesDel score = -0.349224.
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.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1599516 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74962 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.216. BayesDel score = -0.349224.
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.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107256617, n = 1 times).
This variant does not lie in a statistically significant hotspot.