Clinical characteristics: Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome.

Diagnosis/testing: The diagnosis of Lynch syndrome is established in a proband by identification on molecular genetic testing of a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or of an EPCAM deletion.

Management: Treatment of manifestations: Adenomas of colon: complete endoscopic polypectomy with follow-up colonoscopy every one to two years. For colon cancer, segmental or extended colonic resection is indicated depending on clinical scenario and factors such as age. For individuals with rectal adenocarcinoma, proctectomy or total proctocolectomy is indicated. Other tumors are managed as in the general population.

Prevention of primary manifestations: Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure. Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome.

Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between ages 20 and 25 years or two to five years before the earliest CRC diagnosis in the family, whichever is earlier. Annual education for females regarding the symptoms of endometrial and ovarian cancers. Consider transvaginal ultrasound examination and endometrial biopsy every one to two years. Consider upper endoscopy examination every three to five years beginning between ages 30 and 35 years particularly for individuals with a family history of gastric cancer and those of Asian ancestry. Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed. Consider capsule endoscopy and small bowel enterography for distal small bowel cancers. Consider urine analysis with urine cytology to identify microscopic hematuria in those with a family history of urothelial cancer. Consider pancreatic cancer screening in individuals with a family history of pancreatic cancer with alternating endoscopic ultrasound and/or MRI/magnetic resonance cholangiopancreatography.

Agents/circumstances to avoid: High body mass, cigarette smoking, type 2 diabetes, and high cholesterol.

Evaluation of relatives at risk: When a diagnosis of Lynch syndrome has been confirmed in a proband, molecular genetic testing for the Lynch syndrome-related pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Genetic counseling: Lynch syndrome caused by a heterozygous germline pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or by an EPCAM deletion is inherited in an autosomal dominant manner. Individuals with Lynch syndrome caused by constitutional inactivation of MLH1 by methylation typically represent simplex cases but families with non-mendelian inheritance of hypermethylation have been reported. The majority of individuals with Lynch syndrome inherited a pathogenic variant from a parent; however, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant in the family is known.