️ Episode 177: Biallelic MCM8/MCM9 Variants: From Hypogonadism to Cancer Predisposition In this episode of PaperCast Base by Base, we explore a multi‑cohort clinical–genomic study that delineates the phenotype of individuals with biallelic germline variants in MCM8 or MCM9, clarifying links to polyposis and early‑onset cancers in addition to the long‑recognized association with hypogonadism. Study Highlights:Using population datasets (100,000 Genomes Project, UK Biobank, and gnomAD), a curated case series, and tumor sequencing, the authors assessed cancer and reproductive phenotypes among carriers of predicted deleterious variants. They found significant enrichment of biallelic MCM9 variants among participants with colonic and rectal polyps and with gastric cancer in the 100,000 Genomes Project, whereas no similar enrichment was seen for MCM8 or in UK Biobank. Across the aggregated case series (26 biallelic MCM8 and 28 biallelic MCM9 carriers), MCM9—but not MCM8—was associated with polyposis and early‑onset colorectal cancer, while both genes were linked to hypogonadism and to female germ cell tumors presenting in early adolescence. Tumor mutational‑signature analysis predominantly showed clock‑like processes without a consistent pattern of mismatch‑repair or homologous‑recombination deficiency, suggesting that many tumors in carriers are not defined by a distinctive repair‑defect signature. The authors recommend inclusion of MCM8/MCM9 on diagnostic panels for relevant clinical contexts and propose surveillance considerations for biallelic carriers. Conclusion:Biallelic MCM9 variants confer risk for polyposis, gastric cancer, and early‑onset colorectal cancer, and biallelic variants in either MCM8 or MCM9 are consistently linked to hypogonadism and early germ cell tumors, supporting panel inclusion and individualized surveillance strategies. Reference:Helderman, N. C., Yang, T., Palles, C., Terlouw, D., Mei, H., Vorderman, R. H. P., Cats, D., Díaz‑Gay, M., Jongmans, M. C. J., Ramdien, A., van de Beek, I., Eleveld, T. F., Green, A., Hes, F. J., van den Heuvel‑Eibrink, M. M., Van Der Kelen, A., Kliesch, S., Kuiper, R. P., Lakeman, I. M. M., Lashley, L. E. E. L. O., Looijenga, L. H. J., Oud, M. S., Steingröver, J., Tenenbaum‑Rakover, Y., Tops, C. M., Tüttelmann, F., de Voer, R. M., Westra, D., Wyrwoll, M. J., Golubicki, M., Antelo, M., Bonjoch, L., Terradas, M., Valle, L., Alexandrov, L. B., Morreau, H., van Wezel, T., Castellví‑Bel, S., Goldberg, Y., & Nielsen, M. (2025). Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9. *Human Genetics and Genomics Advances*, 6, 100480. https://doi.org/10.1016/j.xhgg.2025.100480 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/