What Are the 31 Genes in the IPSS-M Risk Model for MDS?

If you are looking at a next-generation sequencing (NGS) report, it can be overwhelming to see a long list of tested genes. In the context of Myelodysplastic Syndromes (MDS), the Molecular International Prognostic Scoring System (IPSS-M) is a widely used risk model—not a standalone laboratory test. To calculate a personalized prognostic score, the IPSS-M calculator combines your clinical lab results with 31 specific molecular features (30 gene mutations and one structural change) ^[1].

According to the original 2022 study by Bernard et al. that developed the model, the 31 molecular features used in the official IPSS-M calculation are:
ASXL1, BCOR, BCORL1, CBL, CEBPA, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KRAS, NF1, NPM1, NRAS, PHF6, PRPF8, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2, and KMT2A (specifically a structural alteration called a partial tandem duplication, or PTD) ^[1].

How the IPSS-M Calculates Your Risk

The IPSS-M is not a simple “mutation count” where every mutated gene automatically adds one point to your score. Instead, a specialized digital calculator weighs all of your specific clinical and genetic inputs to determine your individualized risk profile ^[1].

To generate your score, the IPSS-M combines:

• Clinical Variables: The score heavily weights your clinical lab results, including your hemoglobin level, platelet count, absolute neutrophil count (ANC), the percentage of blasts (immature cells in your bone marrow), and your cytogenetics (large-scale chromosomal changes) ^[1][2].
• Selected Gene Mutations: The model only factors in acquired variants within the 31 features that are deemed pathogenic (disease-driving) ^[3].
• Mutation Type and Allelic Status: How a gene is mutated matters. For instance, the model differentiates between a single mutation in the TP53 gene and a “multi-hit” TP53 profile. A multi-hit profile—which can mean two separate mutations, or one mutation combined with a deletion (like 17p deletion) or copy-neutral loss of heterozygosity—is a strong predictor of higher risk ^[1][4].
• Co-mutation Patterns: Some genes interact with each other. A mutation in the SF3B1 gene is statistically associated with a more favorable outcome across large populations, but this benefit is conditional; it can change depending on which other genes are co-mutated ^[1].

The Six Risk Categories

The calculator places patients into one of six categories: Very Low, Low, Moderate Low, Moderate High, High, and Very High ^[1]. These categories estimate population-level outcomes, such as overall survival and the risk of the disease progressing to acute myeloid leukemia (AML) ^[1]. It is vital to remember that these are statistical estimates based on large groups of patients. They are meant to help you and your doctor make shared treatment decisions—they are not personal deadlines or guarantees. Your age, symptoms, comorbidities, and treatment goals also play a massive role in your care.

Why Broad NGS Panels Don’t Always Match Your IPSS-M

Your care team may have ordered a broad commercial NGS panel that tests for 50 to 100+ genes. It is normal to see mutations on your report that are outside the 31-gene IPSS-M list.

If a gene is not on the IPSS-M list, it will not directly change your numerical IPSS-M score ^[1]. However, these “extra” genes still matter clinically. They might help confirm your exact MDS diagnosis, make you eligible for specific targeted therapies or clinical trials, or indicate an inherited risk that affects transplant donor selection.

Conversely, some standard NGS panels may lack the capability to test for specific IPSS-M features. For example, not all tests look for the KMT2A-PTD structural change or the loss of heterozygosity needed to confirm a TP53 multi-hit status.

Glossary for Reading Your Report

To better understand your NGS report, familiarize yourself with these terms:

• Somatic Variant: An acquired mutation that developed during your lifetime in your bone marrow cells (not passed down to children). The IPSS-M relies on these ^[3].
• Germline Variant: An inherited mutation you were born with. While usually excluded from the IPSS-M calculation, finding one may require genetic counseling and can impact family members and transplant planning ^[3].
• Pathogenic Variant: A mutation recognized by experts as actively contributing to the disease ^[3].
• VUS (Variant of Uncertain Significance): A change in the DNA whose impact on your health is not yet known. These are generally not scored as disease-driving mutations ^[3].
• VAF (Variant Allele Frequency): The percentage of sequenced cells that carry a specific mutation.
• Cytogenetics: The study of chromosomes. Certain missing or rearranged chromosomes (like del(5q) or complex karyotypes) are critical, separate inputs into the IPSS-M alongside your gene mutations.