Variant classification summary

NM_002467.5:c.154_156del

MYC · NP_002458.2:p.(Gln52del) · NM_002467.5

GRCh37: chr8:128750604 CCAG>C · GRCh38: chr8:127738358 CCAG>C

Gene: MYC Transcript: NM_002467.5

Final call

VUS

PM1 supporting PM2 moderate PM4 moderate

Variant details

Gene

MYC

Transcript

NM_002467.5

Protein

NP_002458.2:p.(Gln52del)

gnomAD AF

9.304933848123629e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002467.5:c.154_156del (p.Gln52del) is an in-frame deletion of a single amino acid in exon 2 of MYC, encoding the MYC proto-oncogene transcription factor.

2

This variant deletes glutamine at position 52, located within the well-characterized MYC Box I (MB1) transactivation domain (residues 44–63). PM1 (supporting) is applied.

3

The variant is extremely rare in population databases: gnomAD v2.1 allele frequency = 0.0016% (4/249,036 alleles) and gnomAD v4.1 allele frequency = 0.00093% (15/1,612,048 alleles), with no homozygotes observed. PM2 (moderate) is applied.

4

As an in-frame deletion in a non-repeat region resulting in a protein length change (loss of one amino acid), PM4 (moderate) is applied.

5

PVS1 is not met: this in-frame deletion does not qualify as a predicted null variant under the ClinGen SVI PVS1 decision framework (variant bucket: other). Nonsense-mediated decay is not expected.

6

PS3 is not met: no well-established functional studies were identified for this variant. Literature review yielded zero PMIDs with variant-specific data. OncoKB reports unknown oncogenic effect.

7

This variant has been observed 25 times in somatic cancers (COSMIC COSV52368232) but has not been reported in ClinVar. No germline disease associations, de novo events, cosegregation data, or patient phenotypes are available.

8

SpliceAI predicts no splicing impact (max delta score = 0.00). In silico pathogenicity tools (REVEL, BayesDel) are not applicable to deletion variants.

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_002467.5:c.154_156del is an in-frame deletion of a single amino acid (p.Gln52del) and does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus variants). NMD is not expected. PVS1 is not applicable for this variant class under the generic ACMG framework.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant causing the same amino acid change (p.Gln52del) was identified. This variant is absent from ClinVar, and no alternative nucleotide change resulting in the same protein consequence is known to be pathogenic.	clinvar
PS2	Not assessed	No de novo occurrence data are available for this variant. No family studies or parental testing results were identified in the case materials or literature.
PS3	Not met	No well-established in vitro or in vivo functional studies supporting a damaging effect were identified for NM_002467.5:c.154_156del. OncoKB reports unknown oncogenic effect, and no variant-specific functional data were found in the literature. COSMIC observations (n=25) represent somatic occurrence counts, not experimental functional evidence.	oncokb
PS4	Not assessed	No case-control or cohort prevalence data comparing affected versus unaffected individuals are available for this variant.
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No criterion definition available under generic ACMG framework.
PM1	Met	The variant deletes glutamine at position 52, which lies within MYC Box I (MB1, residues 44–63), a well-characterized transactivation domain critical for MYC-mediated transcription and transformation. The in-frame deletion removes a residue from this critical functional domain. The residue-level cancerhotspots.org analysis did not identify a statistically significant hotspot at this position.	oncokb
PM3	N/A	PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. MYC is not associated with a recessive germline disorder; this criterion is not applicable.
PM2	Met	This variant is absent or at extremely low frequency in population databases. In gnomAD v2.1, the allele frequency is 0.0016% (4/249,036 alleles, no homozygotes). In gnomAD v4.1, the allele frequency is 0.00093% (15/1,612,048 alleles, no homozygotes). Both are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	Met	NM_002467.5:c.154_156del is an in-frame 3-nucleotide deletion resulting in the loss of a single amino acid (p.Gln52del) in a non-repeat region of MYC. This protein length change satisfies the PM4 criterion for in-frame deletions in non-repeat regions.
PM5	N/A	PM5 applies to novel missense changes at an amino acid residue where a different missense change has been determined to be pathogenic. NM_002467.5:c.154_156del is an in-frame deletion, not a missense variant. PM5 candidate harvesting was attempted but could not confirm classic same-residue PM5 semantics for this variant class.
PM6	Not assessed	No de novo occurrence data (assumed or confirmed) are available for this variant. No parental testing or family studies were identified.
PP1	Not assessed	No cosegregation data are available for this variant. No family studies were identified in the case materials or literature.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is an established mechanism and benign missense variation is rare. NM_002467.5:c.154_156del is an in-frame deletion, not a missense variant.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL and BayesDel scores are not available for this deletion variant. SpliceAI predicts no significant splice impact (max delta score = 0.00). No HCI prior score is available for MYC. In silico tools designed for missense variants are not informative for in-frame deletions.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar, and OncoKB classifies it as having unknown oncogenic effect.	clinvar oncokb
BA1	Not met	The allele frequency in population databases is well below the 1% BA1 threshold. gnomAD v2.1 AF = 0.0016% and gnomAD v4.1 AF = 0.00093%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency is well below the 0.3% BS1 threshold for non-VCEP adjudication. gnomAD v2.1 AF = 0.0016% and gnomAD v4.1 AF = 0.00093%. No subpopulation exceeds 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygotes are observed in gnomAD v2.1 or v4.1. No evidence that this variant has been observed in a healthy adult individual in the homozygous state or in trans with a known pathogenic variant.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for this variant. No functional data of any kind were found in the literature.
BS4	Not assessed	No cosegregation or family data are available to evaluate lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. NM_002467.5:c.154_156del is an in-frame deletion, not a missense variant.
BP2	Not assessed	No evidence that this variant has been observed in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder.
BP3	Not met	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. The deletion occurs at position 52 within MYC Box I, a well-characterized functional transactivation domain, not in a repetitive region of unknown function.
BP4	Not met	Multiple lines of computational evidence do not conclusively suggest no impact. SpliceAI predicts no splicing impact (max delta = 0.00), but this only addresses splicing. REVEL, BayesDel, and HCI prior are unavailable for this deletion variant. There is insufficient in silico evidence to rule out a deleterious effect on protein function.	spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a case harboring this variant.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar, and OncoKB reports unknown oncogenic effect.	clinvar oncokb
BP7	N/A	BP7 applies to synonymous variants for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the splice enhancer. NM_002467.5:c.154_156del is an in-frame deletion, not a synonymous variant.

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