NM_001033082.2:c.749C>T (p.Pro250Leu) in MYCL is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).1 Multiple in silico predictors (REVEL 0.327, BayesDel -0.06129, SpliceAI max delta 0.01) concordantly suggest a benign effect, providing BP4_Supporting evidence.2 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.3 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).4
MYCL
Final classification
VUS
MYCL c.749C>T · p.Pro250Leu
MYCL
NM_001033082.2:c.749C>T (p.Pro250Leu) in MYCL is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
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
MYCL c.749C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001033082.2 · variants mapped to exon structure
MYCL
NM_001033082.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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).
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
✓
BP4
supporting
Benign
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.
REVEL: 0.327 (benign range)BayesDel: -0.06129 (benign)SpliceAI max delta: 0.01 (no splice impact)
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 250 resulting in the same amino acid change (Pro250Leu) has been reported as pathogenic in ClinVar.
PS2
No de novo observation data with confirmed maternity and paternity is 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.
PS4
No case-control or statistical comparison data are available to support enrichment of this variant in affected individuals versus controls.
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.
PM6
No de novo observation (assumed or confirmed) is available for this variant in any publication or database.
PP1
No co-segregation data from affected families is available for this variant.
PP2
MYCL is a proto-oncogene with limited evidence for missense variants as a predominant germline disease mechanism.
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).
PP4
No patient phenotype or clinical data are available for this case.
PP5
NM_001033082.2:c.749C>T is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from all queried population databases.
BS2
No observation of this variant in healthy adult controls has been reported beyond its absence from gnomAD.
BS3
No well-established functional studies demonstrate a neutral or benign effect for p.Pro250Leu.
BS4
No segregation data are available for this variant.
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.
BP2
No observation of this variant in trans (in cis or compound heterozygous) with a known pathogenic dominant variant has been reported.
BP5
No data are available identifying an alternate molecular cause for the patient's phenotype.
BP6
NM_001033082.2:c.749C>T is absent from ClinVar.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.01). REVEL score = 0.327. BayesDel score = -0.06129.
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. MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links