NM_002467.6:c.779C>A

MYC · NP_002458.2:p.(Pro260Gln) · NM_002467.6

GRCh37: chr8:128751242 C>A · GRCh38: chr8:127738996 C>A

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.(Pro260Gln)

gnomAD AF

5.913279780919555e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002467.6:c.779C>A (p.Pro260Gln) is a missense variant in MYC. It is extremely rare in population databases (gnomAD v4.1 AF=0.000591%, 9/1,521,998 alleles; highest subpopulation Ashkenazi Jewish AF=0.024%), meeting PM2 at supporting level.

Multiple independent in silico prediction tools support a benign interpretation: REVEL score 0.077 (well below pathogenic threshold of 0.5), BayesDel score -0.346 (negative, benign-leaning), and SpliceAI max delta 0.00 (no splicing impact), meeting BP4 at supporting level.

The variant is absent from ClinVar with no functional data, segregation data, de novo reports, or case-control studies available to support any additional pathogenic or benign criteria.

PM2 (supporting pathogenic) and BP4 (supporting benign) offset each other. No other criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 combination rules (PMID:25741868).

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.779C>A is a missense variant (p.Pro260Gln). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at c.779 has been established as pathogenic in ClinVar or the literature. This variant is absent from ClinVar and no same-position comparators with a known pathogenic classification were identified.	clinvar pm5_candidates
PS2	Not met	No de novo observations have been reported for NM_002467.6:c.779C>A. No family-based studies or trio data are available in the evidence packet.
PS3	Not met	No variant-specific functional data are available for NM_002467.6:c.779C>A (p.Pro260Gln). OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence. No publications with functional characterization of this exact variant or a systematically characterized range including position 260 were identified.	oncokb
PS4	Not met	No case-control or cohort studies demonstrating statistically significant enrichment of NM_002467.6:c.779C>A in affected individuals versus controls are available.
PS5	Not met	No alternative missense change at residue Pro260 has been established as pathogenic in ClinVar or the literature. No PM5 candidate comparators were identified.	clinvar pm5_candidates
PM1	Not met	Residue Pro260 is not located within a statistically significant mutational hotspot per cancerhotspots.org. While MYC has well-characterized functional domains, no domain-level characterization specific to position 260 was identified in the evidence packet that would support PM1 application.
PM2	Met	NM_002467.6:c.779C>A is extremely rare in population databases. It is absent from gnomAD v2.1 (0/169,868 alleles) and present at very low frequency in gnomAD v4.1 (9/1,521,998 alleles, AF=0.000591%, grpmax FAF=2.9e-07). The highest subpopulation frequency is in Ashkenazi Jewish (6/25,114, AF=0.024%). All frequencies are well below the 0.1% PM2 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue comparator variants with established pathogenicity were identified. The PM5 candidate search returned zero candidates, and ClinVar is absent for this variant.	clinvar pm5_candidates
PM6	Not met	No de novo observations have been reported for NM_002467.6:c.779C>A. No trio or parentage-confirmed data are available.
PP1	Not met	No co-segregation data are available for NM_002467.6:c.779C>A. No family-based studies were identified.
PP2	Not met	The HCI prior probability database does not support gene MYC (gene_not_supported). Without a gene-specific missense Z-score or constraint metric demonstrating a low rate of benign missense variation, PP2 cannot be applied.
PP3	Not met	Multiple in silico tools predict a benign effect: REVEL score 0.077 (well below the 0.5 pathogenic threshold), BayesDel score -0.346 (negative, benign-leaning), and SpliceAI max delta 0.00 (no splicing impact). Computational evidence does not support a pathogenic role for this variant.	revel bayesdel spliceai
PP4	Not met	No clinical phenotype data are available for the individual carrying NM_002467.6:c.779C>A. The variant cannot be assessed against a disease-specific clinical presentation.
PP5	Not met	NM_002467.6:c.779C>A is absent from ClinVar and has not been classified as pathogenic by any reputable clinical laboratory or expert panel.	clinvar
BA1	Not met	The variant is not common in population databases. The highest observed frequency is 0.024% in the Ashkenazi Jewish subpopulation (gnomAD v4.1), well below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	The variant frequency of 0.024% (Ashkenazi Jewish, gnomAD v4.1) and overall AF of 0.000591% are well below the 0.3% BS1 threshold for a presumed rare disease allele.	gnomad_v4
BS2	Not met	Although NM_002467.6:c.779C>A is observed in gnomAD v4.1 (9 alleles), the very low frequency (0.000591%) is insufficient to invoke BS2. Without a specific disease model, inheritance pattern, and penetrance estimate, observation in a few population database individuals cannot be conclusively interpreted as healthy adult carriers of a fully penetrant allele.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate a neutral or benign effect for NM_002467.6:c.779C>A (p.Pro260Gln). No experimental data are available.
BS4	Not met	No family segregation data are available to assess non-segregation with disease for NM_002467.6:c.779C>A.
BP1	Not met	The PVS1 gene context confirms loss of function is a supported disease mechanism for MYC, but the associated disease literature describes both missense and truncating variants. BP1 requires that truncating variants be the primary known disease mechanism, which is not sufficiently established for MYC based on available evidence.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of NM_002467.6:c.779C>A in trans with a known pathogenic variant. No genotyping data across family members or phased sequence data exist in the evidence packet.
BP4	Met	Multiple lines of computational evidence suggest NM_002467.6:c.779C>A (p.Pro260Gln) has no deleterious impact: REVEL score 0.077 (well below the pathogenic threshold of 0.5), BayesDel score -0.346 (negative, indicating benign), and SpliceAI max delta 0.00 (no predicted splicing alteration). Three independent in silico predictors concur on a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No data are available regarding an alternate molecular basis for disease in an individual carrying NM_002467.6:c.779C>A.
BP6	Not met	NM_002467.6:c.779C>A is absent from ClinVar and has not been classified as benign by any reputable source.	clinvar
BP7	N/A	NM_002467.6:c.779C>A is a missense variant (p.Pro260Gln), not a synonymous variant. BP7 is reserved for synonymous variants with no predicted splice impact.
BP3	N/A	BP3 is trivially not applicable — this is a substitution variant, not an in-frame indel.
PM3	N/A	PM3 is trivially not applicable — no evidence for a recessive disorder model is available for MYC, and no in trans data exist.
PM4	N/A	PM4 is trivially not applicable — this is a substitution variant, not a non-frameshift indel or stop-loss variant.

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