The MUTYH gene is associated with autosomal recessive MUTYH-associated polyposis (MAP) (MedGen UID: 332993). Additionally, evidence of varying degrees suggests a possible association between the MUTYH gene and several cancer types.
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MUTYH is a tumor-suppressor gene important for repairing DNA damage. The MUTYH gene encodes a DNA glycosylase involved in oxidative DNA damage repair. Loss of MUTYH function due to pathogenic variants causes defective DNA repair, leading to accumulation of errors in the DNA sequence as cells continue to divide, thereby increasing the risk of tumor formation.
MedGen UID: 332993
MUTYH-associated polyposis (MAP) is an adult-onset colorectal cancer predisposition syndrome characterized by the growth of tens to hundreds of adenomatous colorectal polyps (PMID: 23035301, 19620482). Features typically present at approximately 47 years of age (PMID: 19506731). Polyp types can include conventional adenomas, as well as serrated adenomas, hyperplastic polyps, and mixed (hyperplastic and adenomatous) polyps (PMID: 18564191). MAP generally has a less severe clinical presentation than familial adenomatous polyposis (FAP)—a clinically similar condition in which hundreds to thousands of colorectal polyps develop (PMID: 20301519, (external) 20301519”:http://www.ncbi.nlm.nih.gov/pubmed/20301519). Individuals with MAP have a 43–100% lifetime risk of developing colorectal cancer (PMID: 23035301, “(external) 19620482”:http://www.ncbi.nlm.nih.gov/pubmed/19620482 National Library of Medicine. Genetics Home Reference: MUTYH gene. Accessed February 2017). Occasionally, colon cancer may develop in the absence of polyposis polyps (PMID: 19245865, 15931596, 19032956).
MAP is also associated with an approximately 4% risk of developing upper gastrointestinal tract cancers including duodenal malignancy secondary to duodenal adenomas, found in 17–25% of affected individuals (PMID: 23035301). Extra-gastrointestinal manifestations are uncommon, but may include jaw-bone cysts and congenital hypertrophy of the retinal pigment epithelium (CHRPE) (PMID: 19732775). It has also been suggested that there is an increased risk of other extraintestinal malignancies such as ovarian, bladder, endometrial, skin, and thyroid cancers (PMID: 19732775, 17956577, 23035301).
MAP occurs in individuals with two pathogenic variants in MUTYH—one in each copy of their MUTYH genes. Individuals with a single MUTYH pathogenic variant are not affected with MAP. Several studies have indicated that the presence of a single pathogenic variant may modify lifetime cancer risks. The risk for colon cancer is not well defined, but large population studies have demonstrated that the risk is modestly increased over the general population (PMID: 19394335). Other studies suggest that the risk for colorectal cancer may be two-to-three times that of the general population (PMID: 19245865, 16492921, 24444654).
There is also evidence suggesting an association between MUTYH and breast cancer in individuals with a single pathogenic variant (PMID: 19732775, 21171015, 21952991, 27194394). Therefore, MUTYH is available as a “preliminary-evidence” gene on the Invitae Breast Cancer Panel and the Invitae Breast and Gyn Cancers Panel. Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes.
MUTYH, formerly known as MYH, is a tumor-suppressor gene that is important for repairing DNA damage. The MUTYH gene encodes a DNA glycosylase involved in oxidative DNA damage repair. Loss of MUTYH function causes defective DNA repair, which leads to an accumulation of errors in the DNA sequence as cells continue to divide, thereby increasing the risk of tumor formation (NCBI Gene. Gene ID:4595 Accessed February 2017).
MAP has autosomal recessive inheritance. Affected individuals have two pathogenic variants—one in each copy of their MUTYH genes. Affected individuals will pass one pathogenic MUTYH variant to all of their children.
Individuals with a single pathogenic variant in the MUTYH gene are considered carriers of MAP. If only one parent is an unaffected carrier, he or she has a 50% risk of passing the pathogenic variant on to each child. If both parents are unaffected carriers, each of their children has a 1 in 4, or 25%, chance of having MAP.
In the Northern European population, 1.5–2% of individuals are carriers of one of two well-described founder variants, c.536A>G (p.Tyr179Cys) in exon 7 and c.1187G>A (p.Gly396Asp) in exon 13 (PMID: 11818965, 12393807, 19245865). Up to 90% of individuals with MAP have one or both of these variants (PMID: 19245865).
Individuals with MAP are best served by seeking care through a clinic with experience treating this condition. Surveillance guidelines for individuals with MAP, as published by the National Comprehensive Cancer Network® (NCCN®), include the following ( NCCN. Genetic/Familial High Risk Assessment: Colorectal. Version 2.2016, accessed January 10, 2017.).
Management for individuals with a single MUTYH pathogenic variant
Medical management and surveillance protocols for individuals with a single pathogenic variant in MUTYH have been developed by the NCCN® ( NCCN. Genetic/Familial High Risk Assessment: Colorectal. Version 2.2016, accessed January 10, 2017.).
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Knowing if pathogenic variants in MUTYH are present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Furthermore, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding MUTYH are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow recommended screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Review date: February 2017
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Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
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