NM_002467.6:c.314G>A (p.Gly105Asp) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at the supporting level.1 Multiple in silico tools predict no significant impact: REVEL score 0.202 (below pathogenicity threshold), BayesDel score -0.0945 (predicts benign), and SpliceAI max delta 0.01 (no splicing impact), meeting BP4 at the supporting level.2 The variant has been reported in somatic cancers (COSMIC COSV52367541, n=5) but without variant-specific functional characterization. No variant-specific functional studies, de novo reports, case-control data, cosegregation data, or ClinVar classifications are available for this variant.3 Under generic ACMG/AMP 2015 combination rules, PM2_Supporting and BP4_Supporting offset each other, yielding no net evidence toward pathogenicity or benignity. The variant is classified as a Variant of Uncertain Significance (VUS).4
MYC
Final classification
VUS
MYC c.314G>A · p.Gly105Asp
MYC
NM_002467.6:c.314G>A (p.Gly105Asp) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at the supporting level.
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.314G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_002467.6 · variants mapped to exon structure
MYC
NM_002467.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_002467.6:c.314G>A is absent from all queried population databases (gnomAD v2.1, v4.1, and gnomAD-Canada v1.0). Under generic ACMG/AMP thresholds, an allele frequency below 0.1% supports PM2 at the supporting level.
Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (genomes + exomes). Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score 0.202 is below the 0.5 pathogenicity threshold. BayesDel score -0.0945 predicts a benign effect. SpliceAI max delta score 0.01 predicts no splicing alteration. Collectively, these in silico tools converge on a neutral or benign prediction.
REVEL 0.202 (below pathogenicity threshold). BayesDel -0.0945 (predicts benign). SpliceAI max delta 0.01 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No pathogenic variant with the same amino acid change (p.Gly105Asp) has been previously established in MYC.
PS2
No de novo occurrence of NM_002467.6:c.314G>A has been reported in a patient with a phenotype consistent with a MYC-associated disorder.
PS3
No variant-specific functional studies have been published that directly test the effect of p.Gly105Asp on MYC transactivation, transformation, or protein interaction.
PS4
No case-control study comparing the frequency of NM_002467.6:c.314G>A in affected individuals versus controls has been published.
PM1
p.Gly105Asp is located within the MYC N-terminal transactivation domain (TAD, residues 1-143), a critical functional region.
PM5
No pathogenic variant with a different amino acid change at codon 105 (Gly105) has been identified in MYC.
PM6
No assumed de novo occurrence has been reported for NM_002467.6:c.314G>A.
PP1
No cosegregation data are available for NM_002467.6:c.314G>A.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease.
PP3
Multiple in silico tools do not support a deleterious effect for NM_002467.6:c.314G>A.
PP4
No patient phenotype or family history information is available for NM_002467.6:c.314G>A.
PP5
No reputable source has classified NM_002467.6:c.314G>A as pathogenic.
Benign
BA1
Allele frequency >1% is required for BA1.
BS1
Allele frequency >0.3% is required for BS1.
BS2
BS2 requires observation in healthy adults (homozygous for recessive, hemizygous for X-linked, or heterozygous for a dominant disorder with full penetrance).
BS3
No well-established functional studies have demonstrated that NM_002467.6:c.314G>A has no deleterious effect on MYC protein function or splicing.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease for NM_002467.6:c.314G>A.
BP1
BP1 requires a missense variant in a gene where only truncating variants cause disease.
BP2
No observation of NM_002467.6:c.314G>A in trans with a known pathogenic MYC variant has been reported.
BP5
BP5 requires observation of NM_002467.6:c.314G>A in a case with an alternate molecular basis for disease.
BP6
No reputable source has classified NM_002467.6:c.314G>A as benign.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.202. BayesDel score = -0.0945134.
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; COSV52367541, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links