Variant classification summary

NM_005378.5:c.868A>G

MYCN · NP_005369.2:p.(Asn290Asp) · NM_005378.5

GRCh37: chr2:16085692 A>G · GRCh38: chr2:15945570 A>G

Gene: MYCN Transcript: NM_005378.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYCN

Transcript

NM_005378.5

Protein

NP_005369.2:p.(Asn290Asp)

gnomAD AF

2.4782686814991047e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant is ultra-rare in gnomAD (max allele frequency 8.8e-06, below the 0.1% threshold) and absent from gnomAD-Canada, with no homozygotes.

2

BP4 (Supporting): REVEL 0.05 and SpliceAI max delta 0.006 both fall below calibrated benign-supporting thresholds, predicting no damaging effect.

3

One supporting pathogenic (PM2) and one supporting benign (BP4) criterion do not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign threshold, yielding Uncertain Significance under generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback: PM2_Supporting + BP4_Supporting is a conflicting combination of one supporting pathogenic and one supporting benign criterion that does not satisfy any combining rule, so the variant is 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	Not applicable: this is a missense substitution, and PVS1 applies only to null variants such as nonsense or frameshift.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing p.(Asn290Asp) with a pathogenic ClinVar classification was available.	clinvar
PS2	Not assessed	Not assessed: no parental testing, trio results, or other de novo evidence for this variant was available.
PS3	Not assessed	Not assessed: no validated functional assay data for this variant was available.
PS4	Not assessed	Not assessed: no case-control or disease-cohort evidence for this variant was available.
PM1	Not met	Not met: a dedicated hotspot lookup found residue 290 does not lie in a statistically significant hotspot.	oncokb
PM2	Met	Met (supporting): absent from gnomAD-Canada with maximum allele frequency 8.8e-06, far below the 0.1% threshold, and no homozygotes.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: PM3 requires a recessive disorder, but MYCN germline disease is autosomal dominant.
PM4	N/A	Not applicable: this missense variant does not change protein length, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 290 previously classified pathogenic was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no report of this variant as presumed de novo was available.
PP1	Not assessed	Not assessed: no family segregation data or relative genotype results were available.
PP2	Not assessed	Not assessed: no missense constraint metric or evidence on MYCN's missense disease mechanism was available.
PP3	Not met	Not met: REVEL 0.05 is well below the 0.644 damaging-prediction threshold, and SpliceAI predicts no splice impact.	revel spliceai
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnosis data was provided.
PP5	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic classification exists.	clinvar
BA1	Not met	Not met: the highest population allele frequency is 3.4e-06, far below the >1% stand-alone benign threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: observed allele frequencies are ultra-rare, well below the threshold for a benign frequency in a rare Mendelian disorder.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: zero homozygotes were observed, but no phenotype-annotated healthy-carrier dataset was available.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no assay data demonstrating normal protein function for this variant was available.
BS4	Not assessed	Not assessed: no unaffected relatives with confirmed absence of the variant were documented.
BP1	Not assessed	Not assessed: no evidence on whether missense variants are a common cause of MYCN germline disease was available.
BP2	Not assessed	Not assessed: no trans/cis genotype or phase information was available.
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions; this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL 0.05 (below the 0.183 threshold) and SpliceAI max delta 0.006 (below 0.2) both predict no damaging effect.	revel spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate molecular cause for the phenotype was available.
BP6	Not met	Not met: the exact variant is absent from ClinVar, so no expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this is a missense substitution.	generic_acmg_combination_rules

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.