About MYCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYCL c.749C>T, p.(Pro250Leu)
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_001033082.2:c.749C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes). Under generic ACMG framework, absence from population databases supports a pathogenic interpretation at supporting strength (PM2).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact: REVEL score 0.327 (below 0.5 pathogenic threshold), BayesDel score -0.06129 (benign-predicting), and SpliceAI max delta score 0.01 (no predicted splice alteration). These concordant benign predictions from independent in silico tools support a benign interpretation at supporting strength.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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. MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 20 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001033082.2:c.749C>T (p.Pro250Leu) in MYCL is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
Multiple in silico predictors (REVEL 0.327, BayesDel -0.06129, SpliceAI max delta 0.01) concordantly suggest a benign effect, providing BP4_Supporting evidence.
The variant is absent from ClinVar and has not been observed in COSMIC or cancerhotspots.org. No variant-specific functional or clinical studies were identified in the literature.
Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), PM2_Supporting is offset by BP4_Supporting. With one supporting pathogenic and one supporting benign criterion, the evidence is insufficient for classification — the variant remains a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_001033082.2:c.749C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes). Under generic ACMG framework, absence from population databases supports a pathogenic interpretation at supporting strength (PM2). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact: REVEL score 0.327 (below 0.5 pathogenic threshold), BayesDel score -0.06129 (benign-predicting), and SpliceAI max delta score 0.01 (no predicted splice alteration). These concordant benign predictions from independent in silico tools support a benign interpretation at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.327 (benign range)
- BayesDel: -0.06129 (benign)
- SpliceAI max delta: 0.01 (no splice impact)
- All three in silico tools concordantly predict benign/no impact
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 250 resulting in the same amino acid change (Pro250Leu) has been reported as pathogenic in ClinVar. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no pathogenic comparator at codon 250 with a different nucleotide change producing p.Pro250Leu
Sources
PS2 No de novo observation data with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data identified across literature or database sources
Still missing
- No pedigree or trio sequencing data available for this variant
PS3 No well-established functional studies have directly tested NM_001033082.2:c.749C>T (p.Pro250Leu) or a systematically characterized range that includes this position. OncoKB classifies the variant as 'Unknown Oncogenic Effect.' No variant-specific functional publications were identified. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence identified
Still missing
- No functional studies available for p.Pro250Leu in MYCL
Sources
PS4 No case-control or statistical comparison data are available to support enrichment of this variant in affected individuals versus controls. The variant is absent from gnomAD, precluding any odds ratio calculation. Details ▾Hide ▴
Evidence considered
- Variant is absent from population databases — no case-control comparison possible
Still missing
- No affected-vs-control statistical data available
PM1 Residue Pro250 does not lie in a statistically significant mutational hotspot per cancerhotspots.org, and no well-characterized critical functional domain has been demonstrated to be disrupted by this specific missense change in the literature. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- no hotspot at position 250
Still missing
- No domain-level functional data specific to position 250 in MYCL
PM6 No de novo observation (assumed or confirmed) is available for this variant in any publication or database. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- No trio or parent-of-origin data available
PP1 No co-segregation data from affected families is available for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No multigenerational pedigree data for this variant
PP2 MYCL is a proto-oncogene with limited evidence for missense variants as a predominant germline disease mechanism. The gene lacks established constraint metrics for benign missense variation and does not meet the PP2 threshold for genes where missense variants are a well-characterized disease mechanism with low benign missense rate. Details ▾Hide ▴
Evidence considered
- MYCL germline disease mechanism not well-established for missense variants
- no constraint metrics supporting PP2
Still missing
- Insufficient evidence that missense is a common germline mechanism in MYCL
PP3 Multiple in silico predictors suggest a benign effect: REVEL score 0.327 (below 0.5 pathogenicity threshold), BayesDel score -0.06129 (below 0, benign-predicting), and SpliceAI max delta score 0.01 (no predicted splice impact). No HCI prior score is available. Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.327 (benign)
- BayesDel: -0.06129 (benign)
- SpliceAI max delta: 0.01 (no splice effect)
- HCI prior: not available
Sources
PP4 No patient phenotype or clinical data are available for this case. PP4 requires a phenotype highly specific for the gene/disease, which cannot be assessed without clinical information. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available for this case
Still missing
- No clinical phenotype information provided
PP5 NM_001033082.2:c.749C>T is absent from ClinVar. No reputable source, including expert panels, has reported this variant as pathogenic. PP5 requires a prior pathogenic classification from a credible source. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no prior pathogenic classification
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population allele frequency is effectively 0%, far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0%
- gnomAD v4.1 AF: 0%
- gnomAD-Canada AF: 0%
Sources
BS1 The variant is absent from all queried population databases. Allele frequency is effectively 0%, far below the BS1 threshold of >0.3% for non-VCEP frameworks. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: 0%
- gnomAD v4.1 AF: 0%
- gnomAD-Canada AF: 0% — all below 0.3% threshold
Sources
BS2 No observation of this variant in healthy adult controls has been reported beyond its absence from gnomAD. BS2 requires documented observation in healthy individuals, which is not available. Details ▾Hide ▴
Evidence considered
- No specific healthy adult carrier data available
Still missing
- No healthy adult genotype data beyond population databases
BS3 No well-established functional studies demonstrate a neutral or benign effect for p.Pro250Leu. OncoKB classifies the variant as 'Unknown Oncogenic Effect.' No functional publications characterizing this variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies showing benign effect
Still missing
- No functional assays available to demonstrate neutral/benign effect
Sources
BS4 No segregation data are available for this variant. BS4 requires lack of co-segregation with disease in affected families, which cannot be assessed without pedigree data. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No pedigree data to assess co-segregation
BP1 While the PVS1 gene-level assessment suggests loss-of-function may be a germline mechanism for MYCL, the disease mechanism is not established as exclusively truncating. BP1 requires that the gene primarily causes disease through truncating variants, which is not well-supported for MYCL. Evidence is insufficient to apply BP1. Details ▾Hide ▴
Evidence considered
- MYCL disease mechanism is not established as exclusively truncating
- insufficient evidence for BP1
Still missing
- Unclear whether truncating variants are the predominant disease mechanism in MYCL
Sources
pvs1_gene_context
BP2 No observation of this variant in trans (in cis or compound heterozygous) with a known pathogenic dominant variant has been reported. BP2 cannot be applied without trans observation data. Details ▾Hide ▴
Evidence considered
- No trans observation data available
Still missing
- No data on co-occurring variants in trans
BP5 No data are available identifying an alternate molecular cause for the patient's phenotype. BP5 requires documented evidence of a different, confirmed pathogenic variant explaining the clinical presentation. Details ▾Hide ▴
Evidence considered
- No alternate molecular explanation identified
Still missing
- No clinical phenotype or alternate genetic findings available
BP6 NM_001033082.2:c.749C>T is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a prior benign classification from a credible source. Details ▾Hide ▴
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001033082.2:c.749C>T is a missense variant (p.Pro250Leu) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to missense variants under the generic ACMG framework. Details ▾Hide ▴
Evidence considered
- Missense variant c.749C>T (p.Pro250Leu) — not a null variant
- apply_generic_pvs1_framework = false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans; no trans-phase data exist and MYCL-associated disease is not established as autosomal recessive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length changes from indels, stop-loss, or initiation codon variants; this variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo candidate same-residue comparator variants with prior pathogenic classification were identified. PM5 candidate harvesting was automatically skipped due to inability to confirm classic same-residue semantics. Details ▾Hide ▴
Evidence considered
- pm5_candidates: 0 same-residue candidates
- total 0 candidates
- recommendation level: not_applicable
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame indels in repetitive regions; this variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_001033082.2:c.749C>T is a missense variant resulting in p.Pro250Leu, not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- c.749C>T is a missense (non-synonymous) substitution
PS5 N/AThis variant is absent from ClinVar; no reputable source has reported it as pathogenic. PS5 requires a prior reputable classification which does not exist. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar — no prior pathogenic classification from any submitter
Sources
Identifiers
- Gene
- MYCL
- Transcript
- NM_001033082.2
- Coding (HGVS c.)
- NM_001033082.2:c.749C>T
- Protein (HGVS p.)
- NP_001028254.2:p.(Pro250Leu)
- GRCh38
- chr1:39897808 G>A
- GRCh37
- chr1:40363480 G>A
Gene diagram
Every interpreted variant in MYCL, mapped onto the exon structure of NM_001033082.2. Select a row to find it on the plot.
MYCLNM_001033082.2
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 MYCL
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.327
- BayesDel
- -0.061
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact: REVEL score 0.327 (below 0.5 pathogenic threshold), BayesDel score -0.06129 (benign-predicting), and SpliceAI max delta score 0.01 (no predicted splice alteration). These concordant benign predictions from independent in silico tools support a benign interpretation at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.327 (benign range)
- BayesDel: -0.06129 (benign)
- SpliceAI max delta: 0.01 (no splice impact)
- All three in silico tools concordantly predict benign/no impact
Sources
PP3 Multiple in silico predictors suggest a benign effect: REVEL score 0.327 (below 0.5 pathogenicity threshold), BayesDel score -0.06129 (below 0, benign-predicting), and SpliceAI max delta score 0.01 (no predicted splice impact). No HCI prior score is available. Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.327 (benign)
- BayesDel: -0.06129 (benign)
- SpliceAI max delta: 0.01 (no splice effect)
- HCI prior: not available
Sources
BP7 N/ANM_001033082.2:c.749C>T is a missense variant resulting in p.Pro250Leu, not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- c.749C>T is a missense (non-synonymous) substitution
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.327. BayesDel score = -0.06129.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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_001033082.2%3Ac.749C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-40363480-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-39897808-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-39897808-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001033082.2%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/MYCL/P250L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MYCL+c.749C%3ET
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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 = 0.01). REVEL score = 0.327. BayesDel score = -0.06129.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.