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.1 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.2 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.3 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).4
MYC
Final classification
VUS
MYC c.779C>A · p.Pro260Gln
MYC
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.
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.779C>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_002467.6 · variants mapped to exon structure
MYC
NM_002467.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 0/169868 alleles (AF=0).gnomAD v4.1: 9/1
✓
BP4
supporting
Benign
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: 0.077 (benign).BayesDel: -0.346 (benign).SpliceAI: max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.779 has been established as pathogenic in ClinVar or the literature.
PS2
No de novo observations have been reported for NM_002467.6:c.779C>A.
PS3
No variant-specific functional data are available for NM_002467.6:c.779C>A (p.Pro260Gln).
PS4
No case-control or cohort studies demonstrating statistically significant enrichment of NM_002467.6:c.779C>A in affected individuals versus controls are available.
PM1
Residue Pro260 is not located within a statistically significant mutational hotspot per cancerhotspots.org.
PM5
No same-residue comparator variants with established pathogenicity were identified.
PM6
No de novo observations have been reported for NM_002467.6:c.779C>A.
PP1
No co-segregation data are available for NM_002467.6:c.779C>A.
PP2
The HCI prior probability database does not support gene MYC (gene_not_supported).
PP3
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).
PP4
No clinical phenotype data are available for the individual carrying NM_002467.6:c.779C>A.
PP5
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.
Benign
BA1
The variant is not common in population databases.
BS1
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.
BS2
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.
BS3
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).
BS4
No family segregation data are available to assess non-segregation with disease for NM_002467.6:c.779C>A.
BP1
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.
BP2
No data are available regarding observation of NM_002467.6:c.779C>A in trans with a known pathogenic variant.
BP5
No data are available regarding an alternate molecular basis for disease in an individual carrying NM_002467.6:c.779C>A.
BP6
NM_002467.6:c.779C>A is absent from ClinVar and has not been classified as benign by any reputable source.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.91328e-06; MAF= 0.00059%, 9/1521998 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000238911; MAF= 0.02389%, 6/25114 alleles, homozygotes = 0); grpmax FAF= 2.9e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/169868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/13008 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00059%
· 9 / 1,521,998
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
Ashkenazi Jewish 6 / 25,114 |
0.024% |
Remaining individuals 1 / 58,888 |
0.0017% |
European (non-Finnish) 2 / 1,141,846 |
0.00018% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American)
gnomAD v2.1
Absent
· 0 / 169,868
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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 = 0.077. BayesDel score = -0.345932.
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 previously been reported in somatic cancers (COSMIC; COSV52377441, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links