NM_001033082.2:c.749C>T

MYCL · NP_001028254.2:p.(Pro250Leu) · NM_001033082.2

GRCh37: chr1:40363480 G>A · GRCh38: chr1:39897808 G>A

Gene: MYCL Transcript: NM_001033082.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MYCL

Transcript

NM_001033082.2

Protein

NP_001028254.2:p.(Pro250Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001033082.2:c.749C>T (p.Pro250Leu) in MYCL is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).

Multiple in silico predictors (REVEL 0.327, BayesDel -0.06129, SpliceAI max delta 0.01) concordantly suggest a benign effect, providing BP4_Supporting evidence.

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.

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).

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	NM_001033082.2:c.749C>T is a missense variant (p.Pro250Leu) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is not applicable to missense variants under the generic ACMG framework.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at codon 250 resulting in the same amino acid change (Pro250Leu) has been reported as pathogenic in ClinVar. The variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo observation data with confirmed maternity and paternity is available for this variant.
PS3	Not met	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. OncoKB classifies the variant as 'Unknown Oncogenic Effect.' No variant-specific functional publications were identified.	oncokb
PS4	Not met	No case-control or statistical comparison data are available to support enrichment of this variant in affected individuals versus controls. The variant is absent from gnomAD, precluding any odds ratio calculation.
PS5	N/A	This variant is absent from ClinVar; no reputable source has reported it as pathogenic. PS5 requires a prior reputable classification which does not exist.	clinvar
PM1	Not met	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.
PM2	Met	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).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No candidate same-residue comparator variants with prior pathogenic classification were identified. PM5 candidate harvesting was automatically skipped due to inability to confirm classic same-residue semantics.	pm5_candidates
PM6	Not met	No de novo observation (assumed or confirmed) is available for this variant in any publication or database.
PP1	Not met	No co-segregation data from affected families is available for this variant.
PP2	Not met	MYCL is a proto-oncogene with limited evidence for missense variants as a predominant germline disease mechanism. The gene lacks established constraint metrics for benign missense variation and does not meet the PP2 threshold for genes where missense variants are a well-characterized disease mechanism with low benign missense rate.
PP3	Not met	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). No HCI prior score is available. Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data are available for this case. PP4 requires a phenotype highly specific for the gene/disease, which cannot be assessed without clinical information.
PP5	Not met	NM_001033082.2:c.749C>T is absent from ClinVar. No reputable source, including expert panels, has reported this variant as pathogenic. PP5 requires a prior pathogenic classification from a credible source.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Population allele frequency is effectively 0%, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all queried population databases. Allele frequency is effectively 0%, far below the BS1 threshold of >0.3% for non-VCEP frameworks.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in healthy adult controls has been reported beyond its absence from gnomAD. BS2 requires documented observation in healthy individuals, which is not available.
BS3	Not met	No well-established functional studies demonstrate a neutral or benign effect for p.Pro250Leu. OncoKB classifies the variant as 'Unknown Oncogenic Effect.' No functional publications characterizing this variant were identified.	oncokb
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of co-segregation with disease in affected families, which cannot be assessed without pedigree data.
BP1	Not met	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. BP1 requires that the gene primarily causes disease through truncating variants, which is not well-supported for MYCL. Evidence is insufficient to apply BP1.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans (in cis or compound heterozygous) with a known pathogenic dominant variant has been reported. BP2 cannot be applied without trans observation data.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data are available identifying an alternate molecular cause for the patient's phenotype. BP5 requires documented evidence of a different, confirmed pathogenic variant explaining the clinical presentation.
BP6	Not met	NM_001033082.2:c.749C>T is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a prior benign classification from a credible source.	clinvar
BP7	N/A	NM_001033082.2:c.749C>T is a missense variant resulting in p.Pro250Leu, not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions; this variant is a single-nucleotide missense substitution.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans; no trans-phase data exist and MYCL-associated disease is not established as autosomal recessive.
PM4	N/A	PM4 applies to protein-length changes from indels, stop-loss, or initiation codon variants; this variant is a single-nucleotide missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.