NM_002467.6:c.872G>C

MYC · NP_002458.2:p.(Arg291Thr) · NM_002467.6

GRCh37: chr8:128752711 G>C · GRCh38: chr8:127740465 G>C

Gene: MYC Transcript: NM_002467.6

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MYC

Transcript

NM_002467.6

Protein

NP_002458.2:p.(Arg291Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002467.6:c.872G>C (p.Arg291Thr) is a missense variant in MYC, a proto-oncogene located on 8q24.21.

The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_supporting).

Multiple in silico predictors consistently indicate a neutral effect: REVEL 0.106, BayesDel -0.388, SpliceAI max delta 0.00 (BP4_supporting).

The variant is absent from ClinVar and has not been reported in the literature, including COSMIC; no functional, segregation, or case-control data are available.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, yielding an ACMG/AMP 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_002467.6:c.872G>C is a missense variant (p.Arg291Thr) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision framework (PMC6185798) does not apply to this variant class.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No different pathogenic missense variant at the same amino acid position (Arg291) has been reported in ClinVar or the literature.	clinvar
PS2	Not met	No de novo data are available for this variant.
PS3	Not met	No variant-specific functional data are available. OncoKB reports unknown oncogenic effect with no variant-level reviewed functional evidence. No publications containing functional characterization of p.Arg291Thr or any systematic range including this residue were identified.	oncokb
PS4	Not met	No case-control or population-based studies comparing this variant in affected versus unaffected individuals are available.
PS5	Not met	No linkage analysis or statistical genetic evidence associating this variant with disease has been reported.
PM1	Not met	p.Arg291 does not lie within a statistically significant mutational hotspot per cancerhotspots.org. Although MYC contains well-characterized functional domains (bHLH at residues ~355–410, leucine zipper at ~410–439), Arg291 resides in the central linker region outside these established critical domains, and no domain-level functional characterization exists for this residue.
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 population databases, indicating it is a rare variant.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 applies to recessive disorders when the variant is detected in trans with a pathogenic variant; no phase or genotype data are available for assessment.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants that change protein length; this is a missense substitution.
PM5	Not met	No pathogenic variant at the same codon (Arg291) has been identified in ClinVar. The PM5 candidate search returned zero same-residue comparator variants.	clinvar pm5_candidates
PM6	Not met	No de novo observation (without confirmation of paternity and maternity) has been reported for this variant.
PP1	Not met	No cosegregation data are available for this variant.
PP2	Not met	HCI prior scores are not available for MYC (gene not supported by the HCI prior database). There is insufficient evidence to establish that MYC has a low rate of benign missense variation in the germline.
PP3	Not met	Multiple in silico predictors are benign-leaning: REVEL score 0.106 (below typical pathogenic threshold of 0.5), BayesDel score -0.387599 (negative, favoring benign), and SpliceAI max delta 0.00 (no predicted splice impact). These results do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available for evaluation.
PP5	Not met	This variant is absent from ClinVar; no reputable source has classified it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%), far below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%), far below the 0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data available regarding observation of this variant in healthy adult individuals.
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect exist for this specific variant.
BS4	Not met	No segregation data are available to evaluate lack of cosegregation with disease.
BP1	Not met	MYC is a proto-oncogene where gain-of-function (amplification, overexpression) is the primary established disease mechanism in cancer; it is not a gene for which primarily truncating variants are known to cause disease.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported.
BP3	N/A	This is a missense variant; BP3 applies to in-frame deletions/insertions in repetitive regions.
BP4	Met	Multiple lines of in silico evidence consistently predict a neutral or benign effect: REVEL score 0.106 (well below pathogenic threshold), BayesDel score -0.387599 (negative, favoring benign), and SpliceAI max delta score 0.00 (no predicted splicing impact).	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternative molecular basis for disease has been reported.
BP6	Not met	This variant is absent from ClinVar; no reputable source has classified it as benign.	clinvar
BP7	N/A	This is a missense variant (p.Arg291Thr), not a synonymous variant; BP7 applies only to synonymous variants without predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.