CDH1 on 16q22.1 encodes E-cadherin which functions in intercellular adhesion. E-cadherin is involved in transmitting chemical signals and controlling cell maturation and movement, and acts as a tumor suppressor. A lack of functional E-cadherin impairs cell adhesion and increases the likelihood of invasion and metastasis of tumor cells. Invasive lobular breast cancer (ILC) accounts for 10-15% of invasive breast cancers and is characterized by loss of E-cadherin expression due to mutations, loss of heterozygosity and hypermethylation. Germline CDH1 mutations have been found to cause a familial cancer disorder called hereditary diffuse gastric cancer (HDGC). CDH1 mutation identification in HDGC families has important clinical implications for gastric and breast cancers risk assessment in unaffected family members. The estimated risk for invasive lobular carcinoma in females with germline CDH1 mutations is approximately 40% by age 80 years. Prognostic and therapeutic implications of this alteration remain to be fully elucidated. The 50 gene panel hotspot assay cannot distinguish between germline or somatic (acquired) variants. Correlation with other clinical and lab findings, including genetic counseling, may be helpful, if clinically indicated.