| Gene Name / Alteration | Mutation Type | Frequency / Prevalence | Molecular Effects | Clinical Associations | Key References |
|---|---|---:|---|---|---|
| **MED12** | Recurrent **somatic** exon 2 point mutations; typically heterozygous, gain-of-function–like driver alterations disrupting Mediator kinase module signaling | ~50–80% of uterine fibroids; ~70% in several recent summaries; 77% in a large review | Disrupts MED12-dependent activation of **CDK8/CDK19** within the Mediator complex; associated with altered chromatin landscape, enhancer engagement, genomic instability, progesterone responsiveness, and dysregulated **WNT/β-catenin**, hedgehog, sex steroid, and **TGF-β** signaling; transcriptomic enrichment for ECM/collagen pathways | Most common driver; often multiple tumors rather than solitary lesions; commonly seen even in small tumors; more frequent in Black women in some series; mutant tumors can differ in size/location and may show mutation-status–dependent response to GnRH agonists and ulipristal acetate | (pqac-00000001, pqac-00000008, pqac-00000009) |
| **HMGA2 / HMGA1** | **Somatic** overexpression and chromosomal rearrangements/fusions involving HMGA2/1 | ~10% of fibroids in recent overview; in cellular leiomyoma, HMGA2 overexpression was 36.5% and rearrangement 13.2% | Alters chromatin architecture and transcriptional programs; defines a molecular subtype distinct from MED12-mutant tumors | Associated with distinct histopathologic phenotypes; important subtype in usual leiomyoma and especially enriched in some variants such as cellular leiomyoma | (pqac-00000001, pqac-00000005, pqac-00000012) |
| **FH** | **Somatic or germline-related** loss-of-function / deficiency; part of FH-deficient leiomyoma spectrum and HLRCC-related disease | Less common than MED12/HMGA2 in unselected fibroids; recognized recurrent subtype | Fumarate hydratase deficiency rewires metabolism and contributes to a distinct molecular subtype of leiomyoma | Seen in FH-deficient leiomyomas and in hereditary leiomyomatosis and renal cell cancer (HLRCC); clinically relevant for identifying syndromic disease | (pqac-00000001, pqac-00000008, pqac-00000014) |
| **COL4A5 / COL4A6** | Recurrent **somatic deletions / structural alterations** affecting collagen IV genes | Recurrent but uncommon relative to MED12; listed among frequently observed genetic alterations | Likely alters basement-membrane / ECM-related biology and contributes to subtype-specific tumor development | Included among recognized uterine fibroid driver alterations; may overlap with syndromic/structural subtypes rather than classic MED12 tumors | (pqac-00000001, pqac-00000005, pqac-00000008) |
| **SRCAP complex genes** (e.g., **YEATS4, ZNHIT1**, other complex members) | **Inactivating somatic mutations** causing defective H2A.Z loading / chromatin remodeling abnormalities | Recently identified recurrent but uncommon subtype | Produces **H2A.Z deposition defects** and epigenetic dysregulation; supports a chromatin-based pathogenesis distinct from MED12 and HMGA2 | Emerging molecular class of leiomyoma; potentially useful for future subtype-based diagnostics and therapy development | (pqac-00000001, pqac-00000005) |
| **Chromosome 1p deletion** | Recurrent **somatic copy-number loss** | 19.3% in a cellular leiomyoma series | Copy-number loss likely alters dosage of tumor-relevant genes on 1p; appears mutually exclusive with some other driver classes in variant tumors | Particularly reported in **cellular leiomyoma**; useful in variant classification and differential pathology | (pqac-00000012) |
| **24 GWAS risk loci / heritable susceptibility variants** (multiple genes including **GREB1, MCM8** and broader target-gene sets) | **Germline susceptibility SNPs** / risk loci from population genetics | 24 uterine-fibroid–associated risk loci identified in a 2024 integrative analysis; 394 potential target genes, 168 differentially expressed in tumors | Heritable risk variants map largely to noncoding regulatory regions and influence gene regulation through chromatin contacts, eQTL effects, and cell-type–specific regulatory programs | Explains familial aggregation and racial/population risk differences; points to causal cell types and potential preventive/targeted strategies rather than a single monogenic cause | (pqac-00000005) |
| **Non-coding RNA dysregulation linked to driver status** (e.g., miR-21, miR-29, miR-200; H19, MIAT, XIST) | Secondary molecular alterations influenced by driver mutations, race/ethnicity, and hormones rather than classic coding mutations | Commonly dysregulated across fibroids; not a single frequency estimate | Regulates ECM production, proliferation, apoptosis, and inflammation; expression is influenced by **MED12** mutation status and ovarian steroids | Potential biomarker and non-hormonal therapeutic layer; may help explain phenotypic heterogeneity and racial disparities | (pqac-00000014) |


*Table: This table summarizes the principal genetic and molecular alterations implicated in uterine leiomyoma, emphasizing recurrent somatic drivers, inherited susceptibility loci, and their clinical relevance. It is useful for quickly comparing major subtypes, frequencies, and mechanistic consequences across the current evidence base.*