NM_002467.5:c.517G>A

MYC · NP_002458.2:p.(Asp173Asn) · NM_002467.5

GRCh37: chr8:128750980 G>A · GRCh38: chr8:127738734 G>A

Gene: MYC Transcript: NM_002467.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYC

Transcript

NM_002467.5

Protein

NP_002458.2:p.(Asp173Asn)

gnomAD AF

6.197599297935951e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002467.5:c.517G>A (p.Asp173Asn) is a missense variant in exon 2 of MYC. It is present at extremely low frequency in gnomAD population databases (v4.1: 10/1,613,528 alleles, AF=6.20e-6; v2.1: 1/249,292 alleles, AF=4.01e-6), meeting PM2 at supporting strength.

Multiple in silico tools predict a benign impact: REVEL score 0.139 (benign range), BayesDel score -0.607524 (benign), and SpliceAI max delta 0.00 (no splice impact). These concordant predictions meet BP4 at supporting strength.

This variant is absent from ClinVar with no submitters reporting a classification. Two somatic occurrences are recorded in COSMIC (COSV105010327), but these do not inform germline pathogenicity.

No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified for this variant. No publications specifically mention NM_002467.5:c.517G>A.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting at the supporting level. Per ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), this results in 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	Missense variant (c.517G>A, p.Asp173Asn); not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 framework (PMC6185798), the generic PVS1 decision tree does not apply to missense variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic variant at the same amino acid residue (p.Asp173) with a different amino acid change identified. This variant is absent from ClinVar; no comparator exists.	clinvar
PS2	Not met	No de novo evidence available. No publications, ClinVar submissions, or curated databases report a de novo occurrence of this variant. Literature pass identified 0 PMIDs for this variant.	clinvar
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect for NM_002467.5:c.517G>A were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with variant-specific functional data were found.	oncokb
PS4	Not met	No case-control or statistical enrichment data available for this variant in a germline disease context. COSMIC reports 2 somatic cancer occurrences (COSV105010327), but somatic observations do not constitute PS4 evidence for germline variant classification.
PS5	Not met	No alternative source of moderate-strength pathogenic evidence identified. ClinVar contains no classification for this variant and no publications report it as pathogenic.	clinvar
PM1	Not met	Residue p.Asp173 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No known critical functional domain in MYC has been established as lacking benign missense variation in a germline context.
PM2	Met	Extremely low allele frequency in gnomAD population databases: v2.1 exomes AF = 4.01e-6 (1/249,292 alleles), v4.1 joint AF = 6.20e-6 (10/1,613,528 alleles), well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variant with a different pathogenic amino acid change identified. Automatic candidate harvesting was not feasible — unable to confirm classic same-residue PM5 semantics.	pm5_candidates
PM6	Not met	No de novo evidence reported. No publications, ClinVar submissions, or curated databases report a confirmed de novo occurrence of NM_002467.5:c.517G>A with maternity and paternity confirmed.	clinvar
PP1	Not met	No segregation data available. No family studies or co-segregation analysis involving this variant have been reported.
PP2	Not met	PP2 applies when a gene has a high rate of pathogenic missense variants and a low rate of benign missense variation (missense Z-score > 3.09). MYC is a proto-oncogene without an established germline disease gene-disease validity; the rate of benign missense variation in MYC has not been established for a germline context.
PP3	Not met	In silico predictions do not support a deleterious effect. REVEL score 0.139 (benign range, below 0.5 threshold). BayesDel score -0.607524 (benign range). SpliceAI max delta 0.00 (no predicted splice impact). HCI prior not available for MYC. Multiple lines of computational evidence support a neutral/benign impact.	revel bayesdel spliceai
PP4	Not met	No patient phenotype specificity data available. No clinical cases with detailed phenotyping have been reported for this variant in a germline context.
PP5	Not met	No reputable source reports this variant as pathogenic. ClinVar contains no submission or classification for NM_002467.5:c.517G>A.	clinvar
BA1	Not met	Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (Admixed American), well below the 1% BA1 threshold. This variant does not meet BA1 for a benign stand-alone classification by allele frequency.	gnomad_v4
BS1	Not met	Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (0.0033%), well below the 0.3% BS1 threshold. This variant is too rare to meet BS1 strong benign evidence by allele frequency.	gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. There is no established MYC-related germline disorder with confirmed full penetrance against which to evaluate the 10 apparently healthy gnomAD carriers. The gene-disease relationship for MYC in a germline context is limited to literature-based associations without ClinGen curation.	gnomad_v4 pvs1_gene_context
BS3	Not assessed	No well-established functional studies showing no damaging effect for NM_002467.5:c.517G>A were identified. While in silico scores (REVEL 0.139, BayesDel -0.607524) suggest a benign impact, these are computational predictions, not functional assays. No experimental functional data are available.	revel bayesdel
BS4	Not met	No segregation data available. No family studies showing lack of co-segregation with disease have been reported for this variant.
BP1	Not met	BP1 applies to missense variants in genes where only truncating variants cause disease. There is no established MYC germline disorder where the disease mechanism is exclusively truncating. The PVS1 literature search identified some support for LOF as a possible mechanism but this does not establish exclusive truncating pathogenesis.	pvs1_gene_context
BP2	Not met	No evidence of observation in trans with a known pathogenic variant. No cases with confirmed biallelic genotypes involving this variant have been reported.
BP4	Met	Multiple lines of computational evidence predict no damaging effect. REVEL score 0.139 is in the benign range (well below 0.5). BayesDel score -0.607524 supports a benign interpretation. SpliceAI max delta score 0.00 predicts no splicing impact. These concordant predictions from multiple independent algorithms support a benign effect.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in a case harboring this variant, as no clinical cases with phenotype data are available for evaluation.
BP6	Not met	No reputable source reports this variant as benign. ClinVar contains no submission or classification for NM_002467.5:c.517G>A.	clinvar
BP7	N/A	Missense variant (c.517G>A, p.Asp173Asn); BP7 is applicable only to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This is a non-synonymous substitution.

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