EXO1

Inheritance Pattern: AD

Disease ID:MONDO:0005835

Submitter: ClinGen

Exonuclease 1 (EXO1) is a 5’ to 3’ exonuclease, which is required for both DNA mismatch repair and DNA double-strand break (DSB) repair. Although there is no disease associated with *EXO1* in OMIM, there was an early assertion of association with Lynch syndrome. Thus, it was curated for that disorder. **Summary of Genetic Evidence (Case Level):** 0 point In 2001, Wu et al. (PMID: 11375940) first proposed the association of germline *EXO1* variants in autosomal dominant Lynch syndrome by reporting 13 variants (splice site and missense) detected in 14 families with HNPCC or atypical HNPCC. This study also found that these variants did not occur in more than 200 control individuals. However, this study did not exclude germline MLH1, MSH2, and MSH6 mutations from the patients or use large control populations. Co-segregation of EXO1 variants with disease in these families was not tested. Additionally, the results from the first study were questioned by two subsequent publications (PMID: 12517792, 14756672), in which the authors confirmed that several variants observed in the patients with Lynch syndrome in the Wu et al. study were also observed in controls with similar frequencies, including the truncating variant previously proposed to be a disease-causing mutation. In addition, Alam et al. (PMID: 14623461) identified nine individuals carrying heterozygous germline deletions of 1q42.3 that include *EXO1* gene. Theses individuals had multiple cutaneous and uterine leiomyomatosis, but they did not develop colorectal cancer or other Lynch syndrome spectrum cancers. No microsatellite instability (MSI) was detected from the *EXO1*-null skin leiomyomata tissues either. **Overall Summary:** Considering the lack of substantial association in both genetic and experimental studies, there is convincing evidence refuting the gene-disease relationship between *EXO1* and autosomal dominant Lynch syndrome. This gene-disease pair was originally evaluated as disputed on 6/8/2017 by Colon Cancer GCEP. This re-curation was approved by the ClinGen Hereditary Cancer GCEP on 5/26/2023 (SOP Version 9).