About MYC
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYC c.517G>A, p.(Asp173Asn)
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
Extremely low allele frequency in gnomAD population databases: v2.1 exomes AF = 4.01e-6 (1/249,292 alleles), v4.1 joint AF = 6.20e-6 (10/1,613,528 alleles), well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no damaging effect. REVEL score 0.139 is in the benign range (well below 0.5). BayesDel score -0.607524 supports a benign interpretation. SpliceAI max delta score 0.00 predicts no splicing impact. These concordant predictions from multiple independent algorithms support a benign effect.
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; 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
10 / 1,613,528 alleles
gnomAD v4.1: 10 / 1,613,528 alleles. Recorded AF 6.1976e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01136e-06; MAF= 0.00040%, 1/249292 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89822e-06; MAF= 0.00089%, 1/112382 alleles, homozygotes = 0).
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086130118388183, 2/18414 alleles, homozygotes = 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105010327, n = 2 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.
26 criteria with recorded statuses: 2 met · 19 not met · 2 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002467.5:c.517G>A (p.Asp173Asn) is a missense variant in exon 2 of MYC. It is present at extremely low frequency in gnomAD population databases (v4.1: 10/1,613,528 alleles, AF=6.20e-6; v2.1: 1/249,292 alleles, AF=4.01e-6), meeting PM2 at supporting strength.
Multiple in silico tools predict a benign impact: REVEL score 0.139 (benign range), BayesDel score -0.607524 (benign), and SpliceAI max delta 0.00 (no splice impact). These concordant predictions meet BP4 at supporting strength.
This variant is absent from ClinVar with no submitters reporting a classification. Two somatic occurrences are recorded in COSMIC (COSV105010327), but these do not inform germline pathogenicity.
No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified for this variant. No publications specifically mention NM_002467.5:c.517G>A.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is conflicting at the supporting level. Per ACMG/AMP 2015 combination rules (Richards et al., PMID:25741868), this results in a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingExtremely low allele frequency in gnomAD population databases: v2.1 exomes AF = 4.01e-6 (1/249,292 alleles), v4.1 joint AF = 6.20e-6 (10/1,613,528 alleles), well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/249
- 292 alleles
- AF=4.01e-6
- highest subpop NFE AF=8.90e-6
- gnomAD v4.1: 10/1
- 613
- 528 alleles
- AF=6.20e-6
- grpmax FAF=5.53e-6
- highest subpop AMR AF=3.34e-5
- gnomAD-Canada v1.0: absent
Still missing
- Variant is present (10 alleles in v4.1)
- not truly absent
- supports PM2 at supporting strength only
Sources
BP4 SupportingMultiple lines of computational evidence predict no damaging effect. REVEL score 0.139 is in the benign range (well below 0.5). BayesDel score -0.607524 supports a benign interpretation. SpliceAI max delta score 0.00 predicts no splicing impact. These concordant predictions from multiple independent algorithms support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.139 (benign range
- strongly below 0.5 threshold)
- BayesDel: -0.607524 (benign range)
- SpliceAI: max delta 0.00 (no predicted splice alteration)
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No known pathogenic variant at the same amino acid residue (p.Asp173) with a different amino acid change identified. This variant is absent from ClinVar; no comparator exists. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no variation IDs for NM_002467.5:c.517G>A or for any other variant at codon 173
Still missing
- No known pathogenic comparator at Asp173
Sources
PS2 No de novo evidence available. No publications, ClinVar submissions, or curated databases report a de novo occurrence of this variant. Literature pass identified 0 PMIDs for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature
Still missing
- No de novo testing data available
Sources
PS4 No case-control or statistical enrichment data available for this variant in a germline disease context. COSMIC reports 2 somatic cancer occurrences (COSV105010327), but somatic observations do not constitute PS4 evidence for germline variant classification. Details ▾Hide ▴
Evidence considered
- COSMIC: 2 somatic occurrences
- no germline case-control data
Still missing
- No case-control studies for MYC germline variants
PM1 Residue p.Asp173 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No known critical functional domain in MYC has been established as lacking benign missense variation in a germline context. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant
- exact_variant_listed: no
- no established germline mutational hotspot in MYC
PM6 No de novo evidence reported. No publications, ClinVar submissions, or curated databases report a confirmed de novo occurrence of NM_002467.5:c.517G>A with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo observations in available sources
Still missing
- No de novo testing data available
Sources
PP1 No segregation data available. No family studies or co-segregation analysis involving this variant have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data in any available source
Still missing
- No family or segregation studies available
PP2 PP2 applies when a gene has a high rate of pathogenic missense variants and a low rate of benign missense variation (missense Z-score > 3.09). MYC is a proto-oncogene without an established germline disease gene-disease validity; the rate of benign missense variation in MYC has not been established for a germline context. Details ▾Hide ▴
Evidence considered
- No established germline disease mechanism for missense variants in MYC
- PP2 prerequisites not met
Still missing
- No gene-disease validity assessment for MYC germline missense variation
PP3 In silico predictions do not support a deleterious effect. REVEL score 0.139 (benign range, below 0.5 threshold). BayesDel score -0.607524 (benign range). SpliceAI max delta 0.00 (no predicted splice impact). HCI prior not available for MYC. Multiple lines of computational evidence support a neutral/benign impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.139 (low
- below pathogenic threshold)
- BayesDel: -0.607524 (benign)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: gene not supported
Sources
PP4 No patient phenotype specificity data available. No clinical cases with detailed phenotyping have been reported for this variant in a germline context. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available for this variant
Still missing
- No patient-level phenotype data
PP5 No reputable source reports this variant as pathogenic. ClinVar contains no submission or classification for NM_002467.5:c.517G>A. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic assertion from any reputable source
Sources
BA1 Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (Admixed American), well below the 1% BA1 threshold. This variant does not meet BA1 for a benign stand-alone classification by allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 3.34e-5 (AMR)
- well below 1% BA1 threshold
Sources
BS1 Maximum allele frequency in gnomAD v4.1 is 3.34e-5 (0.0033%), well below the 0.3% BS1 threshold. This variant is too rare to meet BS1 strong benign evidence by allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 3.34e-5
- below 0.3% BS1 threshold
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. There is no established MYC-related germline disorder with confirmed full penetrance against which to evaluate the 10 apparently healthy gnomAD carriers. The gene-disease relationship for MYC in a germline context is limited to literature-based associations without ClinGen curation. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 10 carriers
- likely healthy population controls
- No established MYC germline disorder with confirmed full penetrance
Still missing
- No ClinGen-curated MYC germline gene-disease validity
- BS2 cannot be applied without established disorder characteristics
Sources
gnomad_v4 ↗pvs1_gene_context
BS4 No segregation data available. No family studies showing lack of co-segregation with disease have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available
Still missing
- No family studies available
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. There is no established MYC germline disorder where the disease mechanism is exclusively truncating. The PVS1 literature search identified some support for LOF as a possible mechanism but this does not establish exclusive truncating pathogenesis. Details ▾Hide ▴
Evidence considered
- MYC germline disease mechanism is not established as exclusively truncating
- missense variants not excluded
Still missing
- No established MYC germline disease mechanism supporting BP1 exclusivity
Sources
pvs1_gene_context
BP2 No evidence of observation in trans with a known pathogenic variant. No cases with confirmed biallelic genotypes involving this variant have been reported. Details ▾Hide ▴
Evidence considered
- No in trans observations reported
Still missing
- No biallelic genotype data available
BP5 No alternative molecular basis for disease has been identified in a case harboring this variant, as no clinical cases with phenotype data are available for evaluation. Details ▾Hide ▴
Evidence considered
- No clinical cases with alternative molecular diagnoses reported
Still missing
- No clinical case data available
BP6 No reputable source reports this variant as benign. ClinVar contains no submission or classification for NM_002467.5:c.517G>A. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign assertion from any reputable source
Sources
PS5 No alternative source of moderate-strength pathogenic evidence identified. ClinVar contains no classification for this variant and no publications report it as pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no alternative pathogenic assertion from a reputable source
Sources
Not assessed · 2 · no assessment recorded
PS3 No well-established functional studies demonstrating a damaging effect for NM_002467.5:c.517G>A were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with variant-specific functional data were found. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies in literature
Still missing
- No in vitro or in vivo functional data for p.Asp173Asn
- experimental studies would be required to assess impact
Sources
BS3 No well-established functional studies showing no damaging effect for NM_002467.5:c.517G>A were identified. While in silico scores (REVEL 0.139, BayesDel -0.607524) suggest a benign impact, these are computational predictions, not functional assays. No experimental functional data are available. Details ▾Hide ▴
Evidence considered
- In silico predictions suggest benign impact but do not substitute for well-established functional assays per BS3 requirements
Still missing
- No experimental functional assays (e.g.
- reporter assays
- protein binding
- subcellular localization) performed for p.Asp173Asn
Sources
revelbayesdel
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.517G>A, p.Asp173Asn); not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 framework (PMC6185798), the generic PVS1 decision tree does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 173
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/ANo same-residue comparator variant with a different pathogenic amino acid change identified. Automatic candidate harvesting was not feasible — unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- pm5_candidates: found=false
- eligible_for_classic_pm5_search=false
- 0 candidates
Sources
pm5_candidates
BP7 N/AMissense variant (c.517G>A, p.Asp173Asn); BP7 is applicable only to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This is a non-synonymous substitution. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
Identifiers
- Gene
- MYC
- Transcript
- NM_002467.5
- Coding (HGVS c.)
- NM_002467.5:c.517G>A
- Protein (HGVS p.)
- NP_002458.2:p.(Asp173Asn)
- GRCh38
- chr8:127738734 G>A
- GRCh37
- chr8:128750980 G>A
- COSMIC
- COSV105010327
Gene diagram
Every interpreted variant in MYC, mapped onto the exon structure of NM_002467.5. Select a row to find it on the plot.
MYCNM_002467.5
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in MYC
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
10 / 1,613,528 alleles
AF 6.2e-06 · 0 homozygotes · FAF 5.53e-06
gnomAD v2.1
1 / 249,292 alleles
AF 4.01e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-06 · 10 / 1,613,528 alleles · 0 hom · FAF 5.5e-06
| Admixed American2 / 59,946 | 3.3e-05 |
| Remaining individuals1 / 62,466 | 1.6e-05 |
| European (non-Finnish)7 / 1,179,856 | 5.9e-06 |
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 249,292 alleles · 0 hom
| European (non-Finnish)1 / 112,382 | 8.9e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.1976e-06; MAF= 0.00062%, 10/1613528 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33634e-05; MAF= 0.00334%, 2/59946 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01136e-06; MAF= 0.00040%, 1/249292 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89822e-06; MAF= 0.00089%, 1/112382 alleles, homozygotes = 0).
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086130118388183, 2/18414 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.139
- BayesDel
- -0.608
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no damaging effect. REVEL score 0.139 is in the benign range (well below 0.5). BayesDel score -0.607524 supports a benign interpretation. SpliceAI max delta score 0.00 predicts no splicing impact. These concordant predictions from multiple independent algorithms support a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.139 (benign range
- strongly below 0.5 threshold)
- BayesDel: -0.607524 (benign range)
- SpliceAI: max delta 0.00 (no predicted splice alteration)
Sources
PP3 In silico predictions do not support a deleterious effect. REVEL score 0.139 (benign range, below 0.5 threshold). BayesDel score -0.607524 (benign range). SpliceAI max delta 0.00 (no predicted splice impact). HCI prior not available for MYC. Multiple lines of computational evidence support a neutral/benign impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.139 (low
- below pathogenic threshold)
- BayesDel: -0.607524 (benign)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: gene not supported
Sources
BP7 N/AMissense variant (c.517G>A, p.Asp173Asn); BP7 is applicable only to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This is a non-synonymous substitution. 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 = 0.139. BayesDel score = -0.607524.
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
10 / 1,613,528 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_002467.5%3Ac.517G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/8-128750980-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr8-127738734-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/8-127738734-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002467.5%3Ac.517G…
- OncoKB ↗www.oncokb.org/gene/MYC/D173N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=214697340
- 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= 6.1976e-06; MAF= 0.00062%, 10/1613528 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33634e-05; MAF= 0.00334%, 2/59946 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.01136e-06; MAF= 0.00040%, 1/249292 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89822e-06; MAF= 0.00089%, 1/112382 alleles, homozygotes = 0).
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086130118388183, 2/18414 alleles, homozygotes = 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 = 0.139. BayesDel score = -0.607524.
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; COSV105010327, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.