We present a fascinating case of a 57-year-old male with a novel mutation in MLH1 (<i>MLH1:c.1288G > T, p.(Glu430*)</i>), who presented with two synchronous colonic tumours, initially deemed unresectable, and experienced a complete pathological response on neoadjuvant pembrolizumab. The gene discussed is MLH1; the disease is colonic neoplasm.