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DNA polymerase proofreading and mismatch repair deficiency have different microsatellites signatures. Human cells have developed several enzymatic pathways to repair damaged DNA during DNA replication and recombination, such as DNA mismatch repair (MMR), which recognizes and repairs erroneous insertion, deletion, or misincorporation of bases, and DNA polymerase (encoded by POLE and POLD1), which proofreads each nucleotide and excises mismatched nucleotides. Deficiencies of MMR, caused by somatic hypermethylation of the MLH1 promoter or loss of heterozygosity from the germline allele in any one of the MMR genes, can lead to accumulation of microsatellite insertions and deletions known as microsatellite instability (MSI). MSI has been approved as a biomarker for cancer treatment with immune checkpoint inhibitors. In the clinic, MSI is commonly detected by comparing microsatellite lengths of a limited panel of microsatellites at five loci between germline and tumor DNA. ....