NM_002467.5:c.956C>T

MYC · NP_002458.2:p.(Thr319Ile) · NM_002467.5

GRCh37: chr8:128752795 C>T · GRCh38: chr8:127740549 C>T

Gene: MYC Transcript: NM_002467.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MYC

Transcript

NM_002467.5

Protein

NP_002458.2:p.(Thr319Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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).

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	NM_002467.5:c.956C>T is a missense variant (p.Thr319Ile) and does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternate nucleotide change at c.956 resulting in the same amino acid change (p.Thr319) has been reported as pathogenic. No same-codon comparator variants were identified in ClinVar.	clinvar pm5_candidates
PS2	Not met	No de novo occurrence data with confirmed maternity and paternity is available for this variant.
PS3	Not met	No variant-specific or range-based functional data exists for NM_002467.5:c.956C>T (p.Thr319Ile). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no reviewed functional evidence. No publications report experimental characterization of this variant or a systematically characterized range encompassing residue T319.	oncokb
PS4	Not met	No data on variant prevalence in affected individuals versus controls is available. The variant is absent from ClinVar and COSMIC, providing no case-level observations.	clinvar
PS5	Not met	No de novo occurrence data (with or without confirmed parentage) is available for this variant. PS5 is not part of the standard ACMG/AMP 2015 criterion set and is not applicable under the generic framework; regardless, no supporting evidence exists.
PM1	Not met	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). Cancerhotspots.org does not identify this position as a statistically significant hotspot. No evidence that residue 319 constitutes a critical functional domain.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants at codon 319 with established pathogenicity were identified. The automated PM5 candidate harvesting found zero candidates, and ClinVar contains no entries for any nucleotide change at this codon.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence data (without confirmed parentage) is available for this variant.
PP1	Not met	No co-segregation data in affected family members is available for this variant.
PP2	Not met	No HCI prior data is available for MYC (gene not supported in the HCI database). The rate of benign missense variation in MYC has not been established for PP2 application.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.079 (well below the 0.5 threshold for pathogenicity), BayesDel score is -0.588 (negative, predicting benign), and SpliceAI predicts no splice impact (max delta score = 0.00). Computational evidence does not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available to assess whether the clinical presentation is highly specific for an MYC-related disorder.
PP5	Not met	NM_002467.5:c.956C>T is absent from ClinVar; no reputable source has reported this variant as pathogenic. No ClinVar submissions exist for this variant.	clinvar
BA1	Not met	NM_002467.5:c.956C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the BA1 threshold of 1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_002467.5:c.956C>T is absent from gnomAD. The allele frequency does not exceed the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data is available on healthy adult individuals carrying this variant. The variant is absent from all population databases, precluding assessment of observation in healthy controls.	gnomad_v2 gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been performed for this variant. OncoKB reports no reviewed functional evidence.	oncokb
BS4	Not met	No family segregation data is available to assess lack of segregation with disease.
BP1	N/A	No well-established germline disease association has been confirmed for MYC. The papers identified in the PVS1 gene-context search mention MYC only as a downstream target or in connection with other primary disease genes (FBXW7, APC). BP1 requires a gene for which primarily truncating variants are known to cause disease; this cannot be assessed without a definitive MYC germline disease mechanism.	pvs1_gene_context
BP2	Not met	No data on observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant gene is available.
BP3	N/A	In-frame deletions/insertions in a repetitive region without a known function — this is a missense substitution, not an in-frame indel.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data is available on an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	NM_002467.5:c.956C>T is absent from ClinVar; no reputable source has reported this variant as benign. No ClinVar submissions exist for this variant.	clinvar
BP7	N/A	NM_002467.5:c.956C>T is a missense variant (p.Thr319Ile), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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