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
MYC c.517G>A · p.Asp173Asn
MYC
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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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