About MYCL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MYCL c.688A>C, p.(Met230Leu)
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
The variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=1.24e-6; 2/1,614,214 alleles, 0 homozygotes), which is well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign effect: REVEL score 0.196 (below 0.5 deleterious threshold), BayesDel score -0.397591 (negative, strongly favoring benign), and SpliceAI max delta score 0.02 (no predicted splicing impact). The absence of an HCI prior does not negate the concordant benign predictions from available in silico tools.
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
2 / 1,614,214 alleles
gnomAD v4.1: 2 / 1,614,214 alleles. Recorded AF 1.23899e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 · 17 not met · 3 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.688A>C (p.Met230Leu) in MYCL is a missense variant absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.24e-6, 2/1,614,214 alleles).
The variant is absent from ClinVar and has not been reported in COSMIC or any literature linking it to human disease.
Multiple in silico tools predict a benign effect: REVEL score 0.196 (below 0.5 deleterious threshold), BayesDel score -0.397591 (favoring benign), and SpliceAI max delta 0.02 (no splice impact).
PM2 (supporting) is met due to absence from gnomAD v2.1 and extremely low frequency in v4.1. BP4 (supporting) is met based on concordant benign computational predictions. The pathogenic and benign evidence each consist of a single supporting criterion and are balanced.
Applying the generic ACMG/AMP 2015 final classification combination rules (PMID:25741868), a single supporting pathogenic criterion (PM2) and a single supporting benign criterion (BP4) are insufficient to reach likely pathogenic or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF=1.24e-6; 2/1,614,214 alleles, 0 homozygotes), which is well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF 1.24e-06 (2/1
- 614
- 214 alleles
- homozygotes=0)
- gnomAD-Canada: absent
Sources
BP4 SupportingMultiple lines of computational evidence support a benign effect: REVEL score 0.196 (below 0.5 deleterious threshold), BayesDel score -0.397591 (negative, strongly favoring benign), and SpliceAI max delta score 0.02 (no predicted splicing impact). The absence of an HCI prior does not negate the concordant benign predictions from available in silico tools. Details ▾Hide ▴
Evidence considered
- REVEL 0.196 (benign-leaning)
- BayesDel -0.397591 (benign)
- SpliceAI max delta 0.02 (no splice impact)
Sources
Not met · 17 · evaluated, threshold not reached
PS2 No de novo occurrence (with both maternity and paternity confirmed) has been reported for this variant in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature for NM_001033082.2:c.688A>C
Still missing
- No trio or de novo sequencing data available
Sources
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for p.Met230Leu. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence identified
Still missing
- No functional studies evaluating MYCL p.Met230Leu in transcriptional activation
- DNA binding
- or oncogenic transformation assays
Sources
PS4 No case-control studies or enrichment data demonstrate increased prevalence of this variant in affected individuals compared to controls. The variant is absent from COSMIC and not reported in tumor sequencing datasets. Details ▾Hide ▴
Evidence considered
- Absent from COSMIC
- gnomAD v4.1 frequency is 1.24e-6 (2/1
- 614
- 214 alleles) but no affected-vs-control comparison data exists
Still missing
- No case-control or enrichment studies for this variant
Sources
PM1 While p.Met230Leu resides in the C-terminal leucine zipper domain (a functionally important region for MYCL dimerization), no defined mutational hotspot with multiple pathogenic missense variants has been established for MYCL. PM1 requires a well-characterized critical domain supported by enrichment of pathogenic missense changes. Details ▾Hide ▴
Evidence considered
- Variant not in a statistically significant hotspot
- no ClinGen-defined critical domain for MYCL with pathogenic missense enrichment
Still missing
- No curated pathogenic missense cluster data specific to the MYCL leucine zipper domain
Sources
PM6 No assumed de novo occurrence (without confirmation of maternity/paternity) has been reported for this variant in any database or publication. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports identified
Still missing
- No de novo sequencing studies include this variant
Sources
PP1 No cosegregation data are available; no family studies linking this variant to any disease phenotype have been published. Details ▾Hide ▴
Evidence considered
- No cosegregation or family studies identified
Still missing
- No family-based segregation data for MYCL variants
PP3 Multiple in silico tools predict a benign effect for this substitution: REVEL score 0.196 (below the 0.5 deleterious threshold), BayesDel -0.397591 (negative, favoring benign), and SpliceAI max delta 0.02 (no predicted splice impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.196 (benign-leaning)
- BayesDel: -0.397591 (benign)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
PP5 No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic assertion from any clinical laboratory
Sources
BA1 The variant allele frequency in gnomAD v4.1 is 1.24e-6, far below the BA1 threshold of >1% (0.01). BA1 is not met. Details ▾Hide ▴
BS1 The variant allele frequency in gnomAD v4.1 is 1.24e-6, far below the BS1 threshold of >0.3% (0.003). BS1 is not met. Details ▾Hide ▴
BS2 No evidence of this variant observed in a homozygous state in healthy adults. BS2 requires observation in trans with a pathogenic variant or in homozygous state in healthy individuals for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 homozygotes: 0
- no published observations in healthy adults
Still missing
- No homozygous or healthy-adult observations to evaluate
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for p.Met230Leu. No functional studies of any kind were identified for this variant. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- OncoKB reports Unknown Oncogenic Effect
Still missing
- No functional data available for p.Met230Leu
Sources
BS4 No segregation data are available to evaluate lack of segregation with disease. BS4 requires absence of segregation in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No segregation studies available
Still missing
- No family segregation data
BP1 BP1 applies to missense variants in genes where truncating (null) variants are the primary disease mechanism. MYCL is an oncogene in which amplification and overexpression — not truncating loss of function — are the predominant pathogenic mechanisms. A missense change in this gene does not satisfy BP1. Details ▾Hide ▴
Evidence considered
- MYCL is an oncogene with amplification/overexpression as primary mechanism
- no established role for truncating variants
Sources
BP5 No evidence that this variant is observed in a case with an alternative molecular basis for disease. No clinical case data are available. Details ▾Hide ▴
Evidence considered
- No clinical cases with alternative molecular diagnoses reported
Still missing
- No clinical case data available
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 PS5 requires an alternative nucleotide change at the same codon classified as pathogenic by a reputable source. No such comparator exists for codon 230. Details ▾Hide ▴
Not assessed · 3 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same codon to have been previously classified as pathogenic. The variant is absent from ClinVar and no same-residue pathogenic comparator was identified. Details ▾Hide ▴
Evidence considered
- ClinVar has no entries for this variant or any pathogenic variant at codon 230
Still missing
- No pathogenic variant at codon 230 in ClinVar to serve as comparator
Sources
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense is a common disease mechanism. HCI prior data are not available for MYCL; constraint metrics cannot be assessed. Details ▾Hide ▴
Evidence considered
- HCI prior not supported for MYCL
- no gene-level missense constraint data available
Still missing
- No HCI prior or gene-level missense constraint metrics for MYCL
PP4 No patient phenotype or clinical context was provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype information available
Still missing
- No patient phenotype or family history data available for review
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThe variant NM_001033082.2:c.688A>C is a missense change (p.Met230Leu). Under generic ACMG/AMP, PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, single/multi-exon deletion). This missense variant does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Met230Leu) — does not fall into any generic PVS1 null-variant bucket
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 requires detection of the variant in trans with a known pathogenic variant in a recessive disorder. MYCL is not associated with recessive disease; PM3 is intrinsically not applicable. Details ▾Hide ▴
Evidence considered
- MYCL is not a recessive disease gene
PM4 N/APM4 applies only to non-repeat region in-frame insertions/deletions or stop-loss variants. This is a single-nucleotide missense substitution and is intrinsically not applicable. Details ▾Hide ▴
Evidence considered
- Single-nucleotide missense substitution — not an in-frame indel or stop-loss
PM5 N/ANo comparator missense variant at codon 230 (same amino acid residue) with an established pathogenic classification was identified. PM5 candidate harvesting returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparators available
- PM5 candidate search yielded 0 candidates
Sources
pm5_candidates
BP2 N/ABP2 requires observation in trans with a known dominant pathogenic variant, which is only applicable to genes with established recessive inheritance. MYCL is not associated with a recessive disease; BP2 is not applicable. Details ▾Hide ▴
Evidence considered
- MYCL is not a recessive disease gene
- BP2 not applicable
BP3 N/ABP3 applies only to in-frame insertions/deletions in repetitive regions; this is a single-nucleotide substitution and is intrinsically not applicable. Details ▾Hide ▴
Evidence considered
- Single-nucleotide substitution — not an in-frame indel in a repetitive region
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_001033082.2:c.688A>C is a missense variant (p.Met230Leu), not synonymous; BP7 is intrinsically not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Met230Leu) — BP7 only applicable to synonymous variants
Identifiers
- Gene
- MYCL
- Transcript
- NM_001033082.2
- Coding (HGVS c.)
- NM_001033082.2:c.688A>C
- Protein (HGVS p.)
- NP_001028254.2:p.(Met230Leu)
- GRCh38
- chr1:39897869 T>G
- GRCh37
- chr1:40363541 T>G
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
2 / 1,614,214 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,214 alleles · 0 hom
| African/African American1 / 75,048 | 1.3e-05 |
| South Asian1 / 91,088 | 1.1e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, European (non-Finnish).
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23899e-06; MAF= 0.00012%, 2/1614214 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33248e-05; MAF= 0.00133%, 1/75048 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.196
- BayesDel
- -0.398
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign effect: REVEL score 0.196 (below 0.5 deleterious threshold), BayesDel score -0.397591 (negative, strongly favoring benign), and SpliceAI max delta score 0.02 (no predicted splicing impact). The absence of an HCI prior does not negate the concordant benign predictions from available in silico tools. Details ▾Hide ▴
Evidence considered
- REVEL 0.196 (benign-leaning)
- BayesDel -0.397591 (benign)
- SpliceAI max delta 0.02 (no splice impact)
Sources
PP3 Multiple in silico tools predict a benign effect for this substitution: REVEL score 0.196 (below the 0.5 deleterious threshold), BayesDel -0.397591 (negative, favoring benign), and SpliceAI max delta 0.02 (no predicted splice impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.196 (benign-leaning)
- BayesDel: -0.397591 (benign)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_001033082.2:c.688A>C is a missense variant (p.Met230Leu), not synonymous; BP7 is intrinsically not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant p.(Met230Leu) — BP7 only applicable to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.196. BayesDel score = -0.397591.
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
2 / 1,614,214 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
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.688A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-40363541-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-39897869-T-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001033082.2%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/MYCL/M230L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MYCL+c.688A%3EC
- 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= 1.23899e-06; MAF= 0.00012%, 2/1614214 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33248e-05; MAF= 0.00133%, 1/75048 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.196. BayesDel score = -0.397591.
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.