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.1 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.2 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.3 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).4
MYC
Final classification
VUS
PM2BP4
MYC
c.517G>A
p.Asp173Asn
This variant
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MYC c.517G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_002467.5 · variants mapped to exon structure
MYC
NM_002467.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 1/249292 allelesAF=4.01e-6
✓
BP4
supporting
Benign
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: 0.139 (benign rangestrongly below 0.5 threshold)BayesDel: -0.607524 (benign range)
Assessed · not applied
· 18 not met · 2 not assessed
Pathogenic
PS1
No known pathogenic variant at the same amino acid residue (p.Asp173) with a different amino acid change identified.
PS2
No de novo evidence available.
PS3
No well-established functional studies demonstrating a damaging effect for NM_002467.5:c.517G>A were identified.
PS4
No case-control or statistical enrichment data available for this variant in a germline disease context.
PM1
Residue p.Asp173 is not located in a statistically significant mutational hotspot per cancerhotspots.org.
PM6
No de novo evidence reported.
PP1
No segregation data available.
PP2
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).
PP3
In silico predictions do not support a deleterious effect.
PP4
No patient phenotype specificity data available.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (Admixed American), well below the 1% BA1 threshold.
BS1
Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (0.0033%), well below the 0.3% BS1 threshold.
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
No well-established functional studies showing no damaging effect for NM_002467.5:c.517G>A were identified.
BS4
No segregation data available.
BP1
BP1 applies to missense variants in genes where only truncating variants cause disease.
BP2
No evidence of observation in trans with a known pathogenic variant.
BP5
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
No reputable source reports this variant as benign.
N/A · 3
PVS1 · PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.1976e-06; MAF= 0.00062%, 10/1613528 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33634e-05; MAF= 0.00334%, 2/59946 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.01136e-06; MAF= 0.00040%, 1/249292 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89822e-06; MAF= 0.00089%, 1/112382 alleles, homozygotes = 0).
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086130118388183, 2/18414 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00062%
· 10 / 1,613,528
0 hom · FAF 0.00055%
0 hom · FAF 0.00055%
Admixed American 2 / 59,946 |
0.0033% |
Remaining individuals 1 / 62,466 |
0.0016% |
European (non-Finnish) 7 / 1,179,856 |
0.00059% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 249,292
0 hom
0 hom
European (non-Finnish) 1 / 112,382 |
0.00089% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,414
0 hom · FAF 0.003%
0 hom · FAF 0.003%
European (non-Finnish) 2 / 11,736 |
0.017% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.139. BayesDel score = -0.607524.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYC, a transcription factor, is altered by chromosomal rearrangement, amplification and overexpression in a variety of cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105010327, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links