NM_002467.5:c.956C>T (p.Thr319Ile) is a missense variant in MYC exon 3, absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).1 Multiple in silico predictors are concordant in predicting no deleterious effect: REVEL score 0.079, BayesDel score -0.588, and SpliceAI max delta 0.00 (BP4_Supporting).2 The variant is absent from ClinVar with no submissions from any laboratory, and has not been reported in COSMIC or at cancerhotspots.org. No variant-specific functional studies or clinical case reports were identified in the literature.3 Under the ACMG/AMP 2015 generic classification framework, the combination of one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) results in a final classification of Variant of Uncertain Significance (VUS).4
MYC
Final classification
VUS
MYC c.956C>T · p.Thr319Ile
MYC
NM_002467.5:c.956C>T (p.Thr319Ile) is a missense variant in MYC exon 3, absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MYC c.956C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_002467.5 · variants mapped to exon structure
MYC
NM_002467.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_002467.5:c.956C>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for absent/very low frequency (<0.1%) in population databases.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.079 (well below pathogenic threshold), BayesDel score is -0.588 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.00). These results are concordant in predicting a benign effect.
REVEL: 0.079 (lowbenign).BayesDel: -0.588253 (benign).
Assessed · not applied
Pathogenic
PS1
No alternate nucleotide change at c.956 resulting in the same amino acid change (p.Thr319) has been reported as pathogenic.
PS2
No de novo occurrence data with confirmed maternity and paternity is available for this variant.
PS3
No variant-specific or range-based functional data exists for NM_002467.5:c.956C>T (p.Thr319Ile).
PS4
No data on variant prevalence in affected individuals versus controls is available.
PM1
Residue Thr319 lies in the central regulatory region of MYC (residues ~144-354), not in the critical bHLH-LZ DNA-binding domain (residues ~355-439).
PM6
No de novo occurrence data (without confirmed parentage) is available for this variant.
PP1
No co-segregation data in affected family members is available for this variant.
PP2
No HCI prior data is available for MYC (gene not supported in the HCI database).
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for an MYC-related disorder.
PP5
NM_002467.5:c.956C>T is absent from ClinVar; no reputable source has reported this variant as pathogenic.
Benign
BA1
NM_002467.5:c.956C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_002467.5:c.956C>T is absent from gnomAD.
BS2
No data is available on healthy adult individuals carrying this variant.
BS3
No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been performed for this variant.
BS4
No family segregation data is available to assess lack of segregation with disease.
BP2
No data on observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant gene is available.
BP5
No data is available on an alternate molecular basis for disease in a case carrying this variant.
BP6
NM_002467.5:c.956C>T is absent from ClinVar; no reputable source has reported this variant as benign.
N/A · 5
PVS1 · PM5 · BP1 · 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 = 0.00). REVEL score = 0.079. BayesDel score = -0.588253.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links