NM_002467.6:c.314G>A

MYC · NP_002458.2:p.(Gly105Asp) · NM_002467.6

GRCh37: chr8:128750777 G>A · GRCh38: chr8:127738531 G>A

Gene: MYC Transcript: NM_002467.6

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYC

Transcript

NM_002467.6

Protein

NP_002458.2:p.(Gly105Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

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_002467.6:c.314G>A is a missense variant (p.Gly105Asp) and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon deletion (PMC6185798).	pvs1_generic_framework
PS1	Not met	No pathogenic variant with the same amino acid change (p.Gly105Asp) has been previously established in MYC. The variant is absent from ClinVar and no published report of a G105D pathogenic classification was identified.	clinvar
PS2	Not met	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. Parental testing data are absent from ClinVar and the literature.	clinvar
PS3	Not met	No variant-specific functional studies have been published that directly test the effect of p.Gly105Asp on MYC transactivation, transformation, or protein interaction. Gene-level evidence confirms the MYC transactivation domain (residues 1-143) is functionally critical, but no assay includes this exact variant.	oncokb
PS4	Not met	No case-control study comparing the frequency of NM_002467.6:c.314G>A in affected individuals versus controls has been published. The variant is absent from gnomAD but absence alone does not constitute PS4-level evidence.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 variant interpretation framework (Richards et al. 2015, PMID:25741868). No VCEP/CSPEC extension for MYC defines a PS5 criterion.	generic_acmg_combination_rules
PM1	Not met	p.Gly105Asp is located within the MYC N-terminal transactivation domain (TAD, residues 1-143), a critical functional region. However, codon 105 is not a recognized mutational hotspot, and no data on benign variation within this domain are available to satisfy the PM1 requirement of low benign variation in a critical functional domain.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic variant with a different amino acid change at codon 105 (Gly105) has been identified in MYC. The PM5 candidate search retrieved zero same-residue comparator variants from ClinVar.	pm5_candidates clinvar
PM6	Not met	No assumed de novo occurrence has been reported for NM_002467.6:c.314G>A. PM6 requires observation of the variant in a patient where maternity and paternity have not been confirmed.	clinvar
PP1	Not met	No cosegregation data are available for NM_002467.6:c.314G>A. No families with MYC germline variants and multi-generational phenotype data have been reported.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. MYC is not a well-established Mendelian disease gene with characterized benign variation rates; no germline disease registry exists for MYC missense variants.
PP3	Not met	Multiple in silico tools do not support a deleterious effect for NM_002467.6:c.314G>A. REVEL score 0.202 is below the 0.5 threshold for pathogenicity. BayesDel score -0.0945 predicts a benign effect (below 0). SpliceAI max delta score 0.01 predicts no splicing alteration. These lines of evidence do not converge on a damaging prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history information is available for NM_002467.6:c.314G>A. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology, which has not been established for MYC.
PP5	Not met	No reputable source has classified NM_002467.6:c.314G>A as pathogenic. The variant is absent from ClinVar and has not been reported by any clinical diagnostic laboratory.	clinvar
BA1	Not met	Allele frequency >1% is required for BA1. NM_002467.6:c.314G>A is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada v1.0).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency >0.3% is required for BS1. NM_002467.6:c.314G>A is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada v1.0).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	BS2 requires observation in healthy adults (homozygous for recessive, hemizygous for X-linked, or heterozygous for a dominant disorder with full penetrance). NM_002467.6:c.314G>A is absent from all population databases, including healthy control cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	No well-established functional studies have demonstrated that NM_002467.6:c.314G>A has no deleterious effect on MYC protein function or splicing. No variant-specific functional data are available.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease for NM_002467.6:c.314G>A. BS4 requires observation of the variant in an affected family member who does not share the disease phenotype.
BP1	Not met	BP1 requires a missense variant in a gene where only truncating variants cause disease. MYC lacks an established germline disease mechanism exclusively mediated by truncating variants. Without a defined MYC germline disease spectrum, BP1 cannot be satisfied.
BP2	Not met	No observation of NM_002467.6:c.314G>A in trans with a known pathogenic MYC variant has been reported. Biallelic inactivation is not a recognized disease mechanism for MYC.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_002467.6:c.314G>A is a missense substitution.
BP4	Met	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 bayesdel spliceai
BP5	Not met	BP5 requires observation of NM_002467.6:c.314G>A in a case with an alternate molecular basis for disease. No such observation has been reported.
BP6	Not met	No reputable source has classified NM_002467.6:c.314G>A as benign. The variant is absent from ClinVar with zero submissions.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants and intronic variants outside canonical splice sites. NM_002467.6:c.314G>A is a missense variant resulting in p.Gly105Asp.	spliceai

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