The MSH6 gene is a mismatch repair gene that was identified as a colon cancer risk gene on chromosome 2 in 1997 (Miyaki 1997). Deleterious germline mutations in MSH6 make up approximately 7-10% of cases of Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (Peltomaki 2003). Individuals with Lynch syndrome due to MSH6 mutations have an increased risk of colon cancer and endometrial cancer, and they may have an increased risk of ovarian cancer, stomach cancer, and urinary tract cancers (Baglietto 2010, Bonadona 2011). Please visit the Lynch Syndrome GeneReviews page for more information.
Individuals with biallelic (homozygous or compound heterozygous) mutations in MSH6 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 MSH6
Penetrance is gender-specific.
|Age Range||Homozygous Normal||Heterozygous||Homozygous Normal||Heterozygous|
- Miyaki M, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet. 1997, 17:271. PMID: 9354786
- Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003, 21:1174. PMID: 12637487
- Baglietto L, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010, 102:193. PMID: 20028993
- Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011, 305:2304. PMID: 21642682
- 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