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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
2 / 1,614,214
0.00012%
Highest · African/African American
0.0013%
Homozygotes
0
Allele frequency by ancestry — gnomAD v4.1
observed in 2 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| African/African American | 1 / 75,048 | 0.0013% | 0 |
| South Asian | 1 / 91,088 | 0.0011% | 0 |
| Admixed American | 0 / 60,026 | — | — |
| European (Finnish) | 0 / 64,040 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,884 | — | — |
| Middle Eastern | 0 / 6,062 | — | — |
| Ashkenazi Jewish | 0 / 29,606 | — | — |
| European (non-Finnish) | 0 / 1,180,038 | — | — |
“
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).
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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