Abstract Constitutional methylation of the MLH1 promoter is a rare cause of Lynch Syndrome likely to be overlooked in daily clinical practice, as MLH1 methylation is common in sporadic tumors. We present four unrelated Danish and Australian patients with Lynch syndrome phenotypes and constitutional MLH1 methylation including two patients with methylation levels indicating mosaicism. The clinical features, immunohistochemistry, MLH1 promoter methylation status and genomic analysis of probands and family members are presented. The patients varied greatly in their clinical presentation and included multiple tumors, and a breast cancer and a dermal lipofibroma, tumors not classically related to Lynch syndrome. However, these patients are difficult to distinguish from other Lynch patients based on the clinical presentation. Awareness of this rare phenomenon and systematic testing of potential carriers is paramount to detect this condition and crucial to estimate the risk of cancer and optimize care for patients and their families.
Graversen et al. (2026) studied this question.