@article {Morakjmedgenet-2017-104744, author = {Monika Morak and Ayseguel Ibisler and Gisela Keller and Ellen Jessen and Andreas Laner and Daniela Gonzales-Fassrainer and Melanie Locher and Trisari Massdorf and Anke M Nissen and Anna Benet-Pag{\`e}s and Elke Holinski-Feder}, title = {Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation}, elocation-id = {jmedgenet-2017-104744}, year = {2018}, doi = {10.1136/jmedgenet-2017-104744}, publisher = {BMJ Publishing Group Ltd}, abstract = {Background Germline defects in MLH1, MSH2, MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1(CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression.Methods We analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results.Results We detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients{\textquoteright} cDNA.Conclusion We report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/early/2018/02/22/jmedgenet-2017-104744}, eprint = {https://jmg.bmj.com/content/early/2018/02/22/jmedgenet-2017-104744.full.pdf}, journal = {Journal of Medical Genetics} }