Background: MMR deficiency (dMMR) has been reported in 15% of CRC, but with a lower frequency in advanced disease. Most cases are due to sporadic MLH1 promoter hypermethylation (often with BRAF mutations), with a minority reflecting germline mutations in MLH1, MSH2, PMS2, or MSH6 (Lynch Syndrome [LS]). The Revised Bethesda Guidelines (RBG) are one means of selecting individuals at risk of LS for further assessment, but will miss a proportion of cases. Methods: We screened all consenting patients for eligibility for CRC trials recruiting specific genetic aberrations, which included MMR assessment. Results: Of 314 patients, immunohistochemistry (IHC) for MMR protein expression is complete on 171. Staining was reduced/absent in 19.3% of tests, and heterogeneous in 12.1%. The dMMR rate was 6.4%. 2 dMMR patients* were identified as at risk of LS, and referred to genetics by their treating clinician before IHC results were known. However 4 other cases† were not referred, and an underlying predisposition would have been missed without this unbiased approach. 4 patients developed metastatic disease, with none experiencing a partial response to chemotherapy thus far. (Table.) Conclusions: This data is representative of a practice with a high proportion of metastatic disease. It suggests that within oncology, an unbiased screening approach for LS is preferable. Whilst the RBG detect the majority of cases, they may be underutilised as other management issues take precedence in oncology clinics. A cost-effective alternative may be the introduction of a nurse-led programme to identify cases at risk, as is being introduced at our centre. A spectrum of clinical behavior exists amongst metastatic dMMR CRC, and larger numbers will reveal if this affects therapeutic response.