The MLH1 gene is a mismatch repair gene that was identified as a colon cancer risk gene on chromosome 3 in 1994 (Papadopoulos 1994; Bronner 1994). Deleterious germline mutations in MLH1 make up approximately 50% of cases of Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (Peltomaki 2003). Individuals with Lynch syndrome due to MLH1 mutations have an increased risk of colon cancer, endometrial cancer, and several other cancers, including gastric cancer, ovarian cancer, urinary tract cancers, and small bowel cancers, among others (Hampel 2005; Stoffel 2009; Watson 2008).Please visit the Lynch Syndrome GenReviews page for more information.
Individuals with biallelic (homozygous or compound heterozygous) mutations in MLH1 can present with constitutional mismatch repair deficiency, an autosomal recessive disorder characterized by childhood-onset hematological, brain, and colorectal malignancies, along with café-au-lait spots, Lisch nodules, and other clinical features overlapping with neurofibromatosis 1 (Felton 2007; Wimmer 2010).
Affected Phenotypes Included in Penetrance Model
Grouped small bowel cancer
Stomach or gastric cancer
Urinary tract cancers (excluding bladder)
Note: Diagnoses other than those listed above, such as breast cancer, prostate cancer, and pancreatic cancer, are not included in this model.
Coding the Pedigree
Code affected individuals in column 5 of the Excel or plain text file used to build your pedigree.
- Code “2” (affected) for individuals with any of the diagnoses in the affected list.
- Code “1” (unaffected) for individuals who have not had any of the diagnoses in the affected list. Individuals with only breast cancer, prostate cancer, and/or pancreatic cancer should be coded as “1.”
- Code “0” for individuals with uncertain or unknown affected status.
More information on formatting pedigrees can be found here.
Penetrance classes for MLH1
Penetrance is gender-specific.
|Age Range||Homozygous Normal||Heterozygous||Homozygous Normal||Heterozygous|
- Papadopoulos N, et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994, 263:1625. PMID: 8128251
- Bronner CE, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994, 368:258. PMID: 8145827
- Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003, 21:1174. PMID: 12637487
- Hampel H, et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology. 2005, 129:415. PMID: 16083698
- Stoffel E, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009, 137:1621. PMID: 19622357
- Watson P, et al. The risk of extra-colonic, extra-endometrial cancer in Lynch syndrome. Int J Cancer. 2008, 123:444. PMID: 18398828
- Felton KEA, et al. Constitutive deficiency in DNA mismatch repair. 2007, 71:483. PMID: 17539897
- Wimmer K, et al. Constitutional mismatch repair-deficiency syndrome. 2010, 95:699. PMID: 20442441