NM_001033082.2:c.688A>C

MYCL · NP_001028254.2:p.(Met230Leu) · NM_001033082.2

GRCh37: chr1:40363541 T>G · GRCh38: chr1:39897869 T>G

Gene: MYCL Transcript: NM_001033082.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYCL

Transcript

NM_001033082.2

Protein

NP_001028254.2:p.(Met230Leu)

gnomAD AF

1.238993095091481e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	The 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	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.	clinvar
PS2	Not met	No de novo occurrence (with both maternity and paternity confirmed) has been reported for this variant in ClinVar or the literature.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for p.Met230Leu.	oncokb
PS4	Not met	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.	gnomad_v4
PS5	Not met	PS5 requires an alternative nucleotide change at the same codon classified as pathogenic by a reputable source. No such comparator exists for codon 230.	clinvar
PM1	Not met	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.	oncokb
PM2	Met	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 gnomad_v4
PM5	N/A	No comparator missense variant at codon 230 (same amino acid residue) with an established pathogenic classification was identified. PM5 candidate harvesting returned no eligible comparators.	pm5_candidates
PM6	Not met	No assumed de novo occurrence (without confirmation of maternity/paternity) has been reported for this variant in any database or publication.	clinvar
PP1	Not met	No cosegregation data are available; no family studies linking this variant to any disease phenotype have been published.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not met	No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No segregation data are available to evaluate lack of segregation with disease. BS4 requires absence of segregation in multiple affected family members.
BP1	Not met	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.	oncokb
BP2	N/A	BP2 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.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No evidence that this variant is observed in a case with an alternative molecular basis for disease. No clinical case data are available.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 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.
BP3	N/A	BP3 applies only to in-frame insertions/deletions in repetitive regions; this is a single-nucleotide substitution and is intrinsically not applicable.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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