Multiple myeloma: genes and variants

Genes linked to Multiple myeloma

• TP53: Cellular tumor antigen p53

  It coordinates transcriptional responses to DNA damage and other cellular stresses, promoting cell-cycle arrest, senescence, DNA repair, or apoptosis when appropriate. Loss of this tumor-suppressive control is one of the most common events in cancer, while germline pathogenic variants cause Li-Fraumeni syndrome.

  0 disease-causing and 0 uncertain variants in TP53 are linked to Multiple myeloma.

• TUBA1A: Tubulin alpha-1A chain

  An alpha-tubulin chain that pairs with beta-tubulin to build microtubules. Microtubules provide tracks for transport and help shape dividing and migrating cells, making TUBA1A especially important for fetal brain development.

  0 disease-causing and 0 uncertain variants in TUBA1A are linked to Multiple myeloma.

• KMT2C: Histone-lysine N-methyltransferase 2C

  It helps establish enhancer-associated H3K4 methylation and thereby controls lineage-specific transcription together with other COMPASS-family proteins. Somatic loss-of-function alterations are frequent across cancers, while germline variants can cause neurodevelopmental phenotypes.

  2 disease-causing and 0 uncertain variants in KMT2C are linked to Multiple myeloma.

• AURKA: Aurora kinase A

  It coordinates centrosome maturation, spindle assembly, and chromosome segregation during mitosis. Overexpression or amplification can promote chromosomal instability and tumor progression, making its kinase activity a target of anticancer drug development.

  1 disease-causing and 0 uncertain variants in AURKA are linked to Multiple myeloma.

• CRBN: Protein cereblon

  It determines substrate recognition for the CRL4-CRBN ubiquitin ligase and thereby controls degradation of selected cellular proteins. Thalidomide and related drugs bind CRBN and redirect the ligase toward new substrates, a mechanism central to their therapeutic and teratogenic effects.

  1 disease-causing and 0 uncertain variants in CRBN are linked to Multiple myeloma.

• DNMT3A: DNA (cytosine-5)-methyltransferase 3A

  It establishes new DNA methylation patterns during development and hematopoietic differentiation. Somatic variants are common in clonal hematopoiesis and acute myeloid leukemia, while germline variants cause Tatton-Brown-Rahman overgrowth syndrome.

  1 disease-causing and 0 uncertain variants in DNMT3A are linked to Multiple myeloma.

• FAT1: Protocadherin Fat 1

  1 disease-causing and 0 uncertain variants in FAT1 are linked to Multiple myeloma.

• FLT3: Receptor-type tyrosine-protein kinase FLT3

  Its signaling supports survival and expansion of early hematopoietic progenitors. Internal tandem duplications and kinase-domain mutations produce constitutive activity in acute myeloid leukemia and are important prognostic markers and therapeutic targets.

  1 disease-causing and 0 uncertain variants in FLT3 are linked to Multiple myeloma.

• NKX2-1: Homeobox protein Nkx-2.1

  It controls developmental and tissue-specific gene programs in lung, thyroid, and basal ganglia. Haploinsufficiency causes brain-lung-thyroid syndrome, variably combining chorea or developmental movement disorder, neonatal respiratory disease, and thyroid dysfunction.

  1 disease-causing and 0 uncertain variants in NKX2-1 are linked to Multiple myeloma.

• PIK3R2: Phosphatidylinositol 3-kinase regulatory subunit beta

  1 disease-causing and 0 uncertain variants in PIK3R2 are linked to Multiple myeloma.

• YAP1: Transcriptional coactivator YAP1

  When Hippo signaling permits nuclear accumulation, it integrates mechanical, polarity, and growth cues to control proliferation, survival, and organ size. Persistent nuclear YAP activity contributes to many cancers, while germline loss-of-function variants can cause developmental eye abnormalities.

  1 disease-causing and 0 uncertain variants in YAP1 are linked to Multiple myeloma.

Known disease-causing variants in Multiple myeloma

Which prediction tools work for Multiple myeloma

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• PolyPhen-2: 67 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 57 out of 100

Same protein, different disease

• Tatton-Brown-Rahman overgrowth syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Multiple myeloma variants (32 disease-causing).
• Heyn-Sproul-Jackson syndrome is also caused by DNMT3A variants; they fall mostly in different places as the Multiple myeloma variants (5 disease-causing).
• Acute myeloid leukemia is also caused by DNMT3A variants; they fall mostly in different places as the Multiple myeloma variants (5 disease-causing).
• Nephrotic syndrome is also caused by FAT1 variants; they fall mostly in different places as the Multiple myeloma variants (4 disease-causing).
• Acute myeloid leukemia is also caused by FLT3 variants; they fall mostly in different places as the Multiple myeloma variants (7 disease-causing).

Diseases related to Multiple myeloma

• Acute myeloid leukemia, also linked to DNMT3A, FLT3 and TP53
• Gastric cancer, also linked to TP53 and TUBA1A
• Hepatocellular carcinoma, also linked to FLT3 and TP53
• Myelodysplastic syndrome, also linked to CRBN and DNMT3A
• Li-Fraumeni syndrome, also linked to TP53
• Alzheimer disease, also linked to AURKA
• Tubulinopathy, also linked to TUBA1A
• Gastrointestinal stromal tumor, also linked to FLT3
• Autosomal recessive limb-girdle muscular dystrophy, also linked to TUBA1A
• Lissencephaly due to TUBA1A mutation, also linked to TUBA1A
• Nephrotic syndrome, also linked to FAT1
• Tatton-Brown-Rahman overgrowth syndrome, also linked to DNMT3A

Frequently asked questions

Which genes are linked to Multiple myeloma?

In CATVariant, Multiple myeloma is linked to 11 analyzed proteins: TP53 (Cellular tumor antigen p53), TUBA1A (Tubulin alpha-1A chain), KMT2C (Histone-lysine N-methyltransferase 2C), AURKA (Aurora kinase A), CRBN (Protein cereblon), DNMT3A (DNA (cytosine-5)-methyltransferase 3A) and 5 more.

How many genetic variants are linked to Multiple myeloma?

10 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 0 are of uncertain significance or have conflicting reports.

Which uncertain variants in Multiple myeloma look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Multiple myeloma?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.57, based on 9 disease-causing and 756 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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