About MYC
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYC c.779C>A, p.(Pro260Gln)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,521,998 alleles
gnomAD v4.1: 9 / 1,521,998 alleles. Recorded AF 5.91328e-06. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52377441, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/169
- 868 alleles (AF=0).
- gnomAD v4.1: 9/1
- 521
- 998 alleles (AF=0.000591%).
- Highest subpopulation: Ashkenazi Jewish 0.024% (well below 0.1% PM2 cutoff).
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.077 (benign).
- BayesDel: -0.346 (benign).
- SpliceAI: max delta 0.00 (no splice impact).
- Three independent computational methods agree on a benign prediction.
Sources
Not met · 22 · evaluated, threshold not reached
PS1 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. Details ▾Hide ▴
Evidence considered
- ClinVar is empty for this variant
- no pathogenic comparator at c.779 exists.
Sources
clinvar ↗pm5_candidates
PS2 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. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental or trio data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No experimental functional studies of this variant exist.
Sources
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. Details ▾Hide ▴
Evidence considered
- No case-control data available.
Still missing
- No disease association studies for this variant.
PM1 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. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: not a statistically significant hotspot residue.
Still missing
- No domain-level functional characterization of residue 260 in the case evidence.
PM5 No same-residue comparator variants with established pathogenicity were identified. The PM5 candidate search returned zero candidates, and ClinVar is absent for this variant. Details ▾Hide ▴
Evidence considered
- No pathogenic same-residue comparators identified.
Sources
clinvar ↗pm5_candidates
PM6 No de novo observations have been reported for NM_002467.6:c.779C>A. No trio or parentage-confirmed data are available. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental or trio data available.
PP1 No co-segregation data are available for NM_002467.6:c.779C>A. No family-based studies were identified. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family studies available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- no missense constraint metric available.
Still missing
- No gene-specific missense constraint data available.
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). Computational evidence does not support a pathogenic role for this variant. Details ▾Hide ▴
Evidence considered
- REVEL: 0.077 (benign range).
- BayesDel: -0.346 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
PP4 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. Details ▾Hide ▴
Evidence considered
- No phenotype data available.
Still missing
- No clinical phenotype information provided.
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. Details ▾Hide ▴
BA1 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.024% (Ashkenazi Jewish)
- far below 1% BA1 cutoff.
Sources
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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF: 0.024%
- below 0.3% BS1 cutoff.
Sources
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. 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. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 9 alleles at 0.000591% AF.
- No disease-specific penetrance or inheritance model available to interpret these observations.
Still missing
- No disease association or inheritance model established for this variant.
Sources
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). No experimental data are available. Details ▾Hide ▴
Evidence considered
- No functional studies available.
Still missing
- No experimental functional characterization of this variant.
BS4 No family segregation data are available to assess non-segregation with disease for NM_002467.6:c.779C>A. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies available.
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. BP1 requires that truncating variants be the primary known disease mechanism, which is not sufficiently established for MYC based on available evidence. Details ▾Hide ▴
Evidence considered
- MYC-related disease includes missense and truncating variants
- not clearly a primarily truncation-driven gene.
Still missing
- Insufficient evidence to establish that truncating variants are the primary disease mechanism for MYC.
Sources
pvs1_gene_context
BP2 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. Details ▾Hide ▴
Evidence considered
- No in trans observation data available.
Still missing
- No phasing or familial genotype data.
BP5 No data are available regarding an alternate molecular basis for disease in an individual carrying NM_002467.6:c.779C>A. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data available.
Still missing
- No clinical or molecular data on alternate diagnoses.
BP6 NM_002467.6:c.779C>A is absent from ClinVar and has not been classified as benign by any reputable source. Details ▾Hide ▴
PS5 No alternative missense change at residue Pro260 has been established as pathogenic in ClinVar or the literature. No PM5 candidate comparators were identified. Details ▾Hide ▴
Evidence considered
- No pathogenic missense comparator at Pro260 identified in ClinVar.
Sources
clinvar ↗pm5_candidates
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Variant is a substitution producing a single amino acid change
- no null variant mechanism applies.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 is trivially not applicable — no evidence for a recessive disorder model is available for MYC, and no in trans data exist. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 is trivially not applicable — this is a substitution variant, not a non-frameshift indel or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 is trivially not applicable — this is a substitution variant, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Identifiers
- Gene
- MYC
- Transcript
- NM_002467.6
- Coding (HGVS c.)
- NM_002467.6:c.779C>A
- Protein (HGVS p.)
- NP_002458.2:p.(Pro260Gln)
- GRCh38
- chr8:127738996 C>A
- GRCh37
- chr8:128751242 C>A
- COSMIC
- COSV52377441
Gene diagram
Every interpreted variant in MYC, mapped onto the exon structure of NM_002467.6. Select a row to find it on the plot.
MYCNM_002467.6
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MYC
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
9 / 1,521,998 alleles
AF 5.91e-06 · 0 homozygotes · FAF 2.9e-07
gnomAD v2.1
0 / 169,868 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.9e-06 · 9 / 1,521,998 alleles · 0 hom · FAF 2.9e-07
| Ashkenazi Jewish6 / 25,114 | 0.00024 |
| Remaining individuals1 / 58,888 | 1.7e-05 |
| European (non-Finnish)2 / 1,141,846 | 1.8e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American.
gnomAD v2.1
AF 0 · 0 / 169,868 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.077
- BayesDel
- -0.346
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.077 (benign).
- BayesDel: -0.346 (benign).
- SpliceAI: max delta 0.00 (no splice impact).
- Three independent computational methods agree on a benign prediction.
Sources
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). Computational evidence does not support a pathogenic role for this variant. Details ▾Hide ▴
Evidence considered
- REVEL: 0.077 (benign range).
- BayesDel: -0.346 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.077. BayesDel score = -0.345932.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
9 / 1,521,998 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002467.6%3Ac.779C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/8-128751242-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr8-127738996-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/8-127738996-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002467.6%3Ac.779C…
- OncoKB ↗www.oncokb.org/gene/MYC/P260Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=214697128
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52377441, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.