NM_005378.5:c.1340T>C

MYCN · NP_005369.2:p.(Leu447Ser) · NM_005378.5

GRCh37: chr2:16086164 T>C · GRCh38: chr2:15946042 T>C

Gene: MYCN Transcript: NM_005378.5

Final call

VUS

PM1 moderate PM2 supporting

Variant details

Gene

MYCN

Transcript

NM_005378.5

Protein

NP_005369.2:p.(Leu447Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	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.	clinvar
PS2	Not assessed	No de novo occurrence data with confirmed paternity and maternity are available for this variant.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.	clinvar
PS5	Not assessed	This variant has not been reported as pathogenic by a reputable source. It is entirely absent from ClinVar.	clinvar
PM1	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	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.	pm5_candidates clinvar
PM6	Not assessed	No de novo observation (without confirmation of paternity and maternity) has been identified for this variant.
PP1	Not assessed	No co-segregation data are available for NM_005378.5:c.1340T>C. The variant has not been reported in any families.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this variant. No clinical cases have been reported.
PP5	Not assessed	This variant has not been reported as pathogenic by a reputable source. It is entirely absent from ClinVar.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4	Not assessed	No segregation data are available to assess lack of co-segregation with disease.
BP1	Not met	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.
BP2	Not assessed	No evidence of observation in trans with a pathogenic variant is available. MYCN-related disorders are autosomal dominant.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not assessed	This variant has not been reported as benign by a reputable source. It is entirely absent from ClinVar.	clinvar
BP7	N/A	BP7 is reserved for synonymous variants with no predicted splice impact. NM_005378.5:c.1340T>C is a missense variant (p.Leu447Ser).
BP3	N/A	BP3 is reserved for in-frame deletions/insertions in a repetitive region. NM_005378.5:c.1340T>C is a single-nucleotide substitution variant.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.