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).1 The variant is absent from ClinVar and has not been reported in COSMIC or any literature linking it to human disease.2 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).3 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.4 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).5
MYCL
Final classification
VUS
MYCL c.688A>C · p.Met230Leu
MYCL
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).
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.
Classification rationale
PM2
BP4
VUS
MYCL c.688A>C
PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
4
gnomad_v2 ↗gnomad_v4 ↗revelbayesdelspliceai ↗
5
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 · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: absentgnomAD v4.1: AF 1.24e-06 (2/1614
✓
BP4
supporting
Benign
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.
REVEL 0.196 (benign-leaning)BayesDel -0.397591 (benign)SpliceAI max delta 0.02 (no splice impact)
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon to have been previously classified as pathogenic.
PS2
No de novo occurrence (with both maternity and paternity confirmed) has been reported for this variant in ClinVar or the literature.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for p.Met230Leu.
PS4
No case-control studies or enrichment data demonstrate increased prevalence of this variant in affected individuals compared to controls.
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.
PM6
No assumed de novo occurrence (without confirmation of maternity/paternity) has been reported for this variant in any database or publication.
PP1
No cosegregation data are available; no family studies linking this variant to any disease phenotype have been published.
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.
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).
PP4
No patient phenotype or clinical context was provided for this case.
PP5
No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as pathogenic.
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 1.24e-6, far below the BA1 threshold of >1% (0.01).
BS1
The variant allele frequency in gnomAD v4.1 is 1.24e-6, far below the BS1 threshold of >0.3% (0.003).
BS2
No evidence of this variant observed in a homozygous state in healthy adults.
BS3
No well-established in vitro or in vivo functional studies demonstrate no damaging effect for p.Met230Leu.
BS4
No segregation data are available to evaluate lack of segregation with disease.
BP1
BP1 applies to missense variants in genes where truncating (null) variants are the primary disease mechanism.
BP5
No evidence that this variant is observed in a case with an alternative molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · BP2 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,614,214
0 hom
0 hom
African/African American 1 / 75,048 |
0.0013% |
South Asian 1 / 91,088 |
0.0011% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, European (non-Finnish))
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 = 0.02). REVEL score = 0.196. BayesDel score = -0.397591.
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