NM_005378.6:c.865_867delTCC

MYCN · NP_005369.2:p.(Ser289del) · NM_005378.6

GRCh37: chr2:16085682 TTCC>T · GRCh38: chr2:15945560 TTCC>T

Gene: MYCN Transcript: NM_005378.6

Final call

VUS

PM2 supporting PM4 moderate

Variant details

Gene

MYCN

Transcript

NM_005378.6

Protein

NP_005369.2:p.(Ser289del)

gnomAD AF

4.337341036451014e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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	Not met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 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.
PS2	N/A	No de novo occurrence data (paternity and maternity confirmed or unconfirmed) has been reported for this variant in any published study or database.
PS3	N/A	No 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.	oncokb
PS4	Not met	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.	clinvar
PS5	N/A	No reputable source has recently classified this variant as pathogenic. ClinVar reports uncertain significance from a single submitter.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped per adjudication directive.
PM4	Met	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.	pvs1_gene_context
PM5	N/A	PM5 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.	pm5_candidates
PM6	N/A	No de novo occurrence has been reported for this variant. No parent-of-origin testing data are available.
PP1	N/A	No segregation data have been reported for this variant in any affected family members.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	N/A	No 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.
PP5	N/A	No reputable source has recently classified this variant as pathogenic. ClinVar reports a single submission of uncertain significance.
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	N/A	No 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.
BS3	N/A	No well-established functional studies demonstrate that this variant has no deleterious effect on protein function or splicing.
BS4	N/A	No segregation data are available to assess lack of co-segregation with disease in affected family members.
BP1	N/A	BP1 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.
BP2	N/A	No observation of this variant in trans with a known pathogenic variant in MYCN has been reported.
BP3	N/A	BP3 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.
BP4	Not met	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.	spliceai
BP5	N/A	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	N/A	No reputable source has recently classified this variant as benign. ClinVar reports a single uncertain significance submission.
BP7	N/A	BP7 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.

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