DiagnosisMUTYH-associated polyposis (MAP) is suspected in an individual who has:Colonic adenoma count between one and ten before age 40 yearsColonic adenoma and/or hyperplastic polyp count between ten and a few hundred Colonic polyposis (i.e., >100 colonic polyps) in the absence of a germline APC mutation Colorectal cancer (CRC) with the somatic KRAS mutation c.34G>T in codon 12Family history of colon cancer (with or without polyps) consistent with autosomal recessive inheritance The diagnosis of MAP is confirmed by the presence of biallelic MUTYH mutations [Al Tassan et al 2002, Sieber et al 2003]. TestingMolecular testing of tumorsSomatic KRAS mutation. A molecular hallmark of carcinomas caused by MUTYH deficiency is the presence of a specific somatic KRAS mutation (c.34G>T in codon 12) in 64% of MAP CRCs [Lipton et al 2003, Nielsen et al 2006, Nielsen et al 2011]. It has been suggested that somatic KRAS analysis be implemented as a pre-screening test to help select persons with CRC eligible for MUTYH germline molecular genetic testing [van Puijenbroek et al 2008].Microsatellite instability (MSI) (see Lynch Syndrome, Microsatellite instability (MSI) testing of tumor tissue). The majority (61/64) of analyzed CRCs in persons with MAP were microsatellite stable; an MSI-high phenotype is found in only a minority of CRCs (0%-18%, mean: 4%, 3/77) [see review Nielsen et al 2011]. Molecular Genetic Testing Gene. MUTYH is the only gene in which mutations cause MUTYH-associated polyposis. Clinical testingNote: Numbering of mutations varies with the reference sequence used by the laboratory (see Molecular Genetics).Targeted mutation analysis. Two common mutations, c.536A>G (p.Tyr179Cys) in exon 7 and c.1187G>A (p.Gly396Asp) in exon 13, are missense variants carried by approximately 1%-2% of the general population [Al-Tassan et al 2002, Cleary et al 2009]; they account for at least 90% of all MUTYH mutations in northern European populations. Nielsen et al [2009b] identified one or both of these biallelic hotspot (founder) mutations in up to 70% of persons with MAP. Note: To date these mutations have not been found in Korean, Japanese, or Jewish persons of European origin, suggesting the existence of founder mutations and ethnic differentiation [Miyaki et al 2005, Peterlongo et al 2006, Kim et al 2007, Yanaru-Fujisawa et al 2008].
Several other common, probable founder mutations have been reported in different populations (Reference sequences NM_001128425.1, NP_001121897.1):Northern European origin. c.1147delC (p.Ala385Profs*23) [Nielsen et al 2009b]Dutch. c.1214C>T (p.Pro405Leu) [Nielsen et al 2005]Italian. c.1437_1439del (p.Glu480del) [Gismondi et al 2004]British Indian. c.1438G>T (p.Glu480X)Pakistani. p.Tyr104X [Dolwani et al 2007, Khawaja & Payne 2007, Prior & Bridgeman 2010]Spanish, Portuguese, Tunisian. c.1227_1228dup (p.Glu410Glyfs*43) [Gomez-Fernandez et al 2009, Abdelmaksoud-Dammak et al 2012] Japanese, Korean. p.Ala359Val [Kim et al 2007, Yanaru-Fujisawa et al 2008]Table 1. Summary of Molecular Genetic Testing Used in MUTYH-Associated PolyposisView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityMUTYHSequence analysis Sequence variants including c.536A>G and c.1187G>A 2, 3~99% ClinicalTargeted mutation analysis c.536A>G (p.Tyr179Cys), c.1187G>A (p.Gly396Asp) 4See footnote 5Deletion / duplication analysis 6, 7Exonic or whole-gene deletionsUnknown, one reported 81. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Includes the mutations commonly included in targeted mutation analysis panels4. The mutation panel always includes c.536A>G (p.Tyr179Cys) and c.1187G>A (p.Gly396Asp) and may include other mutations depending on the laboratory (reference sequences NM_001048171​.1, NP_001041636​.1). 5. The p.Tyr179Cys and p.Gly396Asp mutations account for upwards of 80% of all MUTYH mutations in persons of northern European heritage, but still a significant number of affected individuals do not have one of these two common missense mutations [Nielsen et al 2009b]. 6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.7. Inclusion of testing for whole-gene deletions or duplications in routine MUTYH mutation may vary by laboratory.8. Recently, two groups reported the same large (>4.2-kb) deletion encompassing exons 4-16 in two different affected individuals [Rouleau et al 2011, Torrezan et al 2011]. The mutation detection rate for exonic or whole-gene deletions or duplications seems small, since such aberrations have not been reported before [see review: Nielsen et al 2011]; however, further investigation is warranted. Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found online [Aretz et al 2012].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Interpretation of test results in a probandThe presence of two germline MUTYH mutations confers an increased risk for colon polyps, colon cancer, and other findings of MUTYH-associated polyposis.Failure to detect two germline mutations in MUTYH by sequence analysis of all 16 exons effectively eliminates the possibility that the proband has biallelic MUTYH mutations. Other possibilities are that the presentation in the proband is: (a) associated with mutations in MUTYH that are not detected by sequence analysis, (b) associated with a mutation in another gene predisposing to polyposis, or (c) the result of non-hereditary factors. Testing Strategy To establish a diagnosis in a proband with suggestive clinical findings. Perform molecular genetic testing of MUTYH [van Puijenbroek et al 2008] in a proband with suggestive clinical findings (i.e., 10 to 500 colonic adenomatous polyps*) if the proband EITHER: Has a family history suggestive of autosomal recessive inheritance;
OR Represents a simplex case (i.e., a single occurrence in a family).*Note: In an individual with more than 100 polyps, molecular genetic testing for an APC germline mutation (causing APC-related polyposis conditions) should be performed prior to MUTYH testing unless the family history strongly supports autosomal recessive inheritance.MUTYH molecular genetic testing is typically performed in the following order: Targeted mutation analysis. Most laboratories, especially in the US, begin with targeted mutation analysis. Individuals should initially be tested for the common mutations found in their ethnic background (see Molecular Genetic Testing, Targeted mutation analysis).Sequence analysis of the entire coding regionIf targeted mutation analysis detects only one mutation, perform sequence analysis. In non-northern European or eastern European individuals, perform sequence analysis since a large proportion are unlikely to have either of the two most common missense mutations (p.Tyr179Cys and p.Gly396Asp) (reviewed in Nielsen et al [2011]).If no mutation is detected by targeted mutation analysis, it still may be appropriate to perform sequence analysis of all exons. Note: Since MUTYH mutations are present in 1%-2% of the population, pseudodominant transmission (the occurrence of MAP in two generations of a non-consanguineous family) does not eliminate the possibility that biallelic MUTYH mutations are present.See Table 2 for the likelihood of identifying biallelic MUTYH mutations by number of polyps.See Table 3 for the likelihood of identifying biallelic MUTYH mutations by age of person with CRCs.Table 2. MUTYH Mutation Detection Frequency by Number of Polyps in Individuals with APC Mutation-Negative PolyposisView in own windowNumber of PolypsMutation Detection Frequency by Number of Polyps1-190% (0/1240)10-194% (37/970) 10-495% (3/62)10-9926% (113/435)20-997% (233/3253) 100-9997%-14% (94/1338 1 and 52/370 2)>10002% (2/119)Review of literature, Nielsen et al [2011], Grover et al [2012]1. Grover et al [2012]2. Nielsen et al [2011]Table 3. Percentage of Persons with CRC with Biallelic MUTYH Mutations by Age at Diagnosis View in own windowPersons with MUTYH Biallelic Mutations Age at Diagnosis of CRC % (n)Range1.1% (29/2605)0.8%-6.2%<50 years0.3% (28/11150)0.0%-0.6%>50 yearsReview of literature, Nielsen et al [2011]CRC = colorectal cancerTo establish a diagnosis in a proband with atypical clinical findings (CRC and no or very few adenomas) [van Puijenbroek et al 2008]: 1.Test tumor tissue for the somatic KRAS2 c.34G >T (p.Gly12Cys) mutation.*2.If positive, perform targeted mutation analysis for the relevant common mutations to detect germline mutations. 3.If a single MUTYH germline mutation is identified, perform MUTYH sequence analysis. *Note: Step 1 testing followed by step 2 testing in a proband with CRC with no or very few polyps is arguably more cost-effective than beginning at step 2. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder but may be at a small risk of developing the disorder. See Clinical Description, MUTYH heterozygotes. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in MUTYH.}

Natural History Colon polyps. Most individuals with MUTYH-associated polyposis (MAP) have between ten and a few hundred polyps with a mean age of presentation of about 50 years. A number of individuals with MAP have been described with colorectal cancer (CRC) and no polyps or only a few polyps [Croitoru et al 2004, Farrington et al 2005, Balaguer et al 2007, Cleary et al 2009]. Persons with MAP can present with conventional adenomas as well as serrated adenomas, hyperplastic polyps, and mixed (hyperplastic and adenomatous) polyps [Sieber et al 2003, Chow et al 2006, Boparai et al 2008, O'Shea et al 2008]. Of note, in eight of 17 persons with MAP one or more hyperplastic polyps and/or sessile serrated adenomas (SSAs) were found. Three of these eight individuals fulfilled the criteria for the hyperplastic polyposis syndrome [Boparai et al 2008]. Colon cancer. In the absence of timely surveillance, the lifetime risk for CRC in MAP ranges between 43% and almost 100% [Sampson et al 2003, Sieber et al 2003, Gismondi et al 2004, Farrington et al 2005, Lubbe et al 2009]. Colon cancers in MAP were found to be right-sided in 29% to 69% of cases [Lipton et al 2003, O’Shea et al 2008, Nielsen et al 2009a]. Metachronous or synchronous colon cancers occur in 23% to 27% of individuals [Lipton et al 2003, Nielsen et al 2009a]. In one report individuals with MAP had better survival on average than controls. Five-year survival for persons with MAP colorectal cancer was 78% (95% confidence interval [CI]: 70%-84%) and for controls was 63% (95% CI: 56%-69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for persons with MAP-associated CRC than for controls (hazard ratio of death: 0.48; 95% CI: 0.32-0.72) [Nielsen et al 2010]. Other features variably present in MUTYH-associated polyposisDuodenal polyps and cancer. Duodenal polyps are found in 17%-25% of individuals with MAP. The lifetime risk for duodenal cancer is approximately 4% (SIR: 129; 95% CI: 16-466) [Sieber et al 2003, Aretz et al 2006, Nielsen et al 2006, Vogt et al 2009]. Gastric fundic gland polyps and gastric cancer. Among 150 patients undergoing endoscopic surveillance, 17 (11%) had gastric lesions. Although a higher risk for gastric cancer was observed than in the general population, the trend was not significant (3 of 150; SIR: 4.2; 95% CI: 0.9-12) [Vogt et al 2009]. Extraintestinal manifestations. According to the study of Vogt et al [2009] of 276 persons with MAP from 181 unrelated families, the incidence of extraintestinal malignancies in persons with MAP was almost twice that of the general population (SIR: 1.9; 95% CI: 1.4-2.5); however, no predominant tumor type or marked shift toward early onset was observed. Approximately 28% of the affected individuals had at least one of the following extraintestinal findings: Ovarian cancer. The incidence was significantly increased [standardized incidence ratio (SIR: 5.7; 95% CI: 1.2-17). Mean age at diagnosis was 51 years.Bladder cancer. The incidence was significantly increased (SIR: 7.2; 95% CI: 2.0-18). Mean age at diagnosis was 61 years.Breast cancer. In women the risk for breast cancer tended to be increased. Mean age at diagnosis was 53 years. Breast cancer was also diagnosed in one male with biallelic MUTYH mutations. Endometrial cancer. Cancer of the endometrium was found in two of 118 women. The mean age at diagnosis was 51 years.Skin findings. Benign and malignant sebaceous gland tumors were found in five of 98 individuals and all of these also presented with the associated polyposis coli phenotype (>20 adenomas). Six of 98 had skin cancers (melanomas, squamous epithelial carcinomas, and basal cell cancers) (SIR: 2.8; 95% CI: 1.5-4.8); another eight had other benign tumors of the skin (fibrous histiocytoma, capillary hemangioma, pilar cyst, dermatofibroma, and follicle cyst).Thyroid findingsTwo cases of thyroid cancer were found in a cohort of 276 persons with MAP; a third case has been reported elsewhere [Ponti et al 2005, Vogt et al 2009]. However, further investigation is warranted.A recent study performed by the Cleveland Clinic revealed that 16 of 24 individuals with biallelic MUTYH mutations had abnormal thyroid ultrasound examinations: 7/16 had multinodular goiter and 6/16 had a single nodule. Three of 24 were diagnosed with papillary thyroid cancer [LaGuardia et al 2011]. Note: This high incidence of thyroid cancer was not found in any other study and may point to possible selection bias. Dental abnormalities. Jaw-bone cysts have been reported in 11 of 276 persons with MAP [Vogt et al 2009].Congenital hypertrophy of retinal pigment epithelium (CHRPE). The estimate of CHRPE in individuals with MAP is about 5.5%; however, this figure may also include misdiagnosis since pigment anomalies of the retina are quite frequent in the general population [Vogt et al 2009].MUTYH heterozygotes. The risk to a heterozygote for a germline MUTYH mutation of developing CRC is unclear: the risk was found to be only marginally increased in large population-based studies (OR: 1.1-1.2 in meta-analyses), whereas family-based studies found a higher risk to heterozygote family members than in the general population (OR: 2-3) [Jones et al 2009, Jenkins et al 2006]. Histology. MAP carcinomas also show a high number of tumor infiltrating lymphocytes, although somewhat less than reported in Lynch-associated cancers [Nielsen et al 2009a].

Genotype-Phenotype Correlations Several studies indicate that homozygosity for the c.536A>G mutation confers risk for a more severe phenotype and earlier age of onset as compared with homozygosity for c.1187G>A; age at onset of CRC is approximately eight years earlier for c.536A>G homozygotes [Lubbe et al 2009, Nielsen et al 2009b, Terdiman 2009, Morak et al 2010].

Differential DiagnosisMUTYH-associated polyposis (MAP) can be distinguished from other inherited polyposis and colon cancer conditions by clinical findings, pathologic findings, mode of inheritance, and molecular genetic testing. Conditions to consider in the differential diagnosis include the following:APC-associated polyposis conditions, caused by mutations in APC, are inherited in an autosomal dominant manner. The two phenotypes observed in APC-related polyposis are:Attenuated familial adenomatous polyposis (AFAP), often the genetic syndrome most closely related in presentation to MAP, is caused by mutations at the 5’ and 3’ ends of APC. Individuals with AFAP have between 0 and 100 (mean: 30) adenomas generally located proximally within the colon, and/or a delayed onset of disease compared to classic FAP. Adenomas of the upper segment of the GI tract may also be present. The risk for colon cancer is increased, with diagnosis of colon cancer typically in the fourth or fifth decade. Familial adenomatous polyposis (FAP) is generally characterized by more than 100 adenomas of the colon with onset at an average age of 16 years. Polyps of the small bowel and fundic gland are also common. Without surgical intervention, colon cancer is inevitable (average age 39 years). Individuals with FAP also have an increased risk for small bowel, gastric, pancreatic, thyroid, CNS, liver, and bile duct cancers. Other findings may include desmoid tumors of the abdomen, supernumerary or missing teeth, osteomas, epidermoid cysts, and CHRPE (congenital hypertrophy of the retinal pigment epithelium).Lynch syndrome (hereditary non-polyposis colon cancer, HNPCC), caused by mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2, confers an increased risk for colon, uterine, ovarian, stomach, small bowel, hepatobiliary tract, urinary tract, brain, and skin cancers. The risk for colon cancer is the highest cancer risk seen in Lynch syndrome (average 80% risk, average age at diagnosis 60 years), and colon tumors generally exhibit microsatellite instability. Inheritance is autosomal dominant.Peutz-Jeghers syndrome (PJS) is characterized by GI hamartomatous polyps and mucocutaneous pigmentation. Polyps are most often in the small bowel. Mucocutaneous pigmentation appears as dark brown to blue spots, and often fade with increasing age. Individuals with PJS also have an increased risk for colon, gastric, breast, lung, pancreas, and sex organ cancers. Mutations in STK11 can be detected in up to 94% of patients [Aretz et al 2005]. Inheritance is autosomal dominant.Juvenile polyposis syndrome (JPS) is characterized by an increased risk for hamartomatous polyps of the GI tract. JPS can be diagnosed clinically by the presence of more than five juvenile polyps of the colon, multiple juvenile polyps throughout the GI tract, or any number of juvenile polyps and a family history of juvenile polyps. The term juvenile reflects the histology of the polyps rather than their age of onset. In about 50% of patients JPS is caused by mutation of either SMAD4 or BMPR1A. Hamartomatous polyps generally present in the small bowel, stomach, colon, and rectum. Juvenile polyps are benign, but malignancies can occur. Individuals with JPS are also at an increased risk for colon, gastric, duodenal, small bowel, pancreatic, and biliary tree cancers. Heterozygotes for a SMAD4 germline mutation are at increased risk for manifestations of hereditary hemorrhagic telangiectasia, in particular visceral arteriovenous malformations. Inheritance is autosomal dominant.PTEN hamartoma tumor syndromes are a collection of autosomal dominant syndromes caused by PTEN mutations. These syndromes include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRB), and Proteus syndrome (PS). CS is characterized by multiple hamartomatous polyps in the GI tract and increased risks for breast, thyroid, uterine, colon, and renal cancers. BRRS is a disorder characterized by GI polyposis, macrocephaly, lipomas of the skin, and pigmented macules of the glans penis. PS is a disorder with variable expressivity, but often involving hamartomatous overgrowth of tissues, connective tissue nevi, epidermal nevi, and hyperostoses. Inheritance is autosomal dominant.Hereditary mixed polyposis syndrome (HMPS) is a rare condition described in only a few families worldwide. This syndrome appears to be inherited in an autosomal dominant manner with an associated locus mapped to 15q13-q14. BMPR1A germline exon deletions were identified in four of eight families [Jaeger et al 2003]. Individuals with HMPS are at an increased risk for adenomatous polyps, juvenile polyps, hyperplastic polyps, and polyps containing mixed histology. These individuals are also at increased risk for colon malignancy [Jaeger et al 2003].Hyperplastic polyposis syndrome (HPS), also known as serrated polyposis, is characterized by hyperplastic polyps of the GI tract. Criteria established by the WHO International Classification of Tumor Definition include (among others) the presence of 30 hyperplastic polyps distributed throughout the colon. Although the exact basis of HPS is debated, deleterious heterozygous germline mutations in PTEN, as well as biallelic germline mutations in MUTYH, have been found in a small number of individuals with HPS [Buchanan et al 2009, Kalady et al 2011].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with MUTYH -associated polyposis (MAP), the following evaluations are recommended:Review of personal medical history with note of features related to MAP: colon polyps with the majority being adenomas, colon cancer, rectal bleeding, abdominal pain and discomfort, bloating, diarrheaColonoscopy and review of pathologyUpper endoscopy and review of pathologyBaseline thyroid ultrasound examination at time of diagnosis as suggested by the Cleveland Clinic study [LaGuardia et al 2011]Medical genetics consultationTreatment of ManifestationsIn general, the treatment regarding gastrointestinal tumors is similar to that of familial adenomatous polyposis (FAP) and atypical familial adenomatous polyposis (AFAP) (see APC-Related Polyposis).Colon polyps and colon cancer. Colonoscopy is effective for surveillance for colon cancer; suspicious polyps should be removed (polypectomy) until polypectomy alone cannot manage the large size and density of the polyps. At that point either subtotal colectomy or proctocolectomy is performed based on polyp features and location [Lipton & Tomlinson 2006, Sampson & Jones 2009].Duodenal polyps. Polyps showing dysplasia or villous changes should be excised during endoscopy. Abnormal thyroid findings should be evaluated by a thyroid specialist to determine what combination of monitoring, surgery, and/or fine needle aspiration (FNA) is appropriate [Cleveland Clinic study: LaGuardia et al 2011]. SurveillanceIndividuals with Biallelic MUTYH Germline MutationsIn the US based on National Comprehensive Cancer Network (NCCN) guidelines [NCCN Guidelines 2012; click for full text (registration required)]:Pancolonoscopy should be performed every one to two years beginning at age 25-30 years. Following surgery, endoscopy of any remaining colon or rectum should be performed every one to two years.Upper endoscopy and side viewing duodenoscopy should be performed every three to five years beginning at age 30-35 years.At this time there is no consensus regarding screening intervals for thyroid abnormalities [LaGuardia et al 2011]. Regarding extraintestinal malignancies, to date no specific surveillance beyond existing protocols that are offered to the general population in most Western countries is recommended.In Europe: Recommended ages at which screening should begin differ based on the consensus meeting in Mallorca [Vasen et al 2008; click for full text (registration or institutional access required)]:Pancolonoscopy beginning at age 18-20 yearsUpper endoscopy with side viewing duodenoscopy beginning at age 25-30 yearsRecommended intervals between screenings depend on disease severity [Spigelman et al 1989]. Individuals Heterozygous for a MUTYH Germline Mutation NCCN guidelines do not propose specific screening recommendations for individuals heterozygous for a MUTYH mutation. Available data suggest that heterozygous relatives of patients with MAP have a two- or at most three-fold increase in their risk for colorectal cancer at an age similar to that in the general population (see Clinical Description, MUTYH heterozygotes). Thus, they are expected to benefit from population screening measures or could be offered average moderate-risk colorectal screening based on their family history [Jones et al 2009].Evaluation of Relatives at RiskIt is appropriate to offer molecular genetic testing for the familial mutations to all sibs of an individual with genetically confirmed MAP, so that morbidity and mortality can be reduced through early diagnosis and treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. MUTYH-Associated Polyposis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDMUTYH1p34​.1A/G-specific adenine DNA glycosylaseMUTYHData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for MUTYH-Associated Polyposis (View All in OMIM) View in own window 604933MutY, E. COLI, HOMOLOG OF; MUTYH 608456FAMILIAL ADENOMATOUS POLYPOSIS, 2; FAP2Molecular Genetic Pathogenesis Somatic mutations in several cancer-related genes have been reported in MAP tumors [Nielsen et al 2009a]; however, KRAS mutations are most prevalent (found in 64% of colon cancers). KRAS (OMIM 190070) is involved primarily in regulating cell division and is a frequently activated oncogene in many different kinds of human tumors. KRAS activating mutations cause Ras to accumulate in the active GTP-bound state by impairing intrinsic GTPase activity and conferring resistance to GTPase-activating proteins [Zenker et al 2007]. The critical regions of KRAS for oncogenic activation include codons 12, 13, 59, 61, and 63 [Grimmond et al 1992]. The reasons for predilection for the specific GGT>TGT transversion in codon 12 of KRAS in MAP colon cancers (and not another G>T transversion in codon 12 or another codon) are not yet understood. Of note, somatic mutations in APC, which have been found in between 14% and 83% of MAP-associated colon cancers [Nielsen et al 2009a], have a preponderance for the AGAA or TGAA motif [Jones et al 2002]. Possible predilection for G>T transition in these specific sequences could reflect a higher susceptibility in these motifs for guanine oxidation or defective recognition and/or repair by mutated MUTYH [Jones et al 2002]; this remains to be clarified.Furthermore, the high frequency of G>T transversions in KRAS2 (mutated in early tumor development) but not in TP53 and SMAD4 (implicated in tumor progression) could indicate a predominant MUTYH effect in early carcinogenesis [Nielsen et al 2009a].Normal allelic variants. Human MUTYH (mutY homolog [Escherichia coli]) has an open reading frame of 16 exons containing 1.9 kb.Multiple transcript variants encoding different isoforms have been found for this gene (www.ncbi.nlm.nih.gov/gene/4595). Numbering of nucleotides and amino acids vary depending upon the reference sequence that the laboratory or publication is using. Following current HGVS recommendations, a coding DNA reference sequence was created from RefSeqGene record NG008189.1, transcript alpha 5, NM_001128425.1, for the description of sequence variants in MUTYH. Due to the choice of the longest MUTYH transcript (NM_001128425.1) as a reference, nucleotide and amino acid numbering after nucleotide position 157 (amino acid 53) may differ by up to 42 nucleotides (14 amino acids). Originally the gene was named MYH. Later, this was replaced by MUTYH because MYH was already in use for another group of genes: the myosin heavy chain genes. Other gene aliases are hMYH, CYP2C, MGC4416, and RP4-534D1. Different protein names are: A/G-specific adenine DNA glycosylase, mutY homolog (E. coli), and hMYH [Out et al 2010].Pathologic allelic variantsTable 4. Selected MUTYH Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein AminoAcid ChangeReference Sequencesc.536A>Gp.Tyr179CysNM_001128425​.1
NP_001121897​.1c.1187G>Ap.Gly396Aspc.1418C>Ap.Ala473AspSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). Normal gene product. The MUTYH protein, A/G-specific adenine DNA glycosylase, plays a major role in DNA damage repair, specifically base excision repair, caused by ionizing radiation, various chemical oxidants, and reactive oxygen species generated during aerobic metabolism. In humans, the most mutagenic species from oxidative damage is 8-oxo7,8-dihydro2’deoxyguanosine (8-oxo-dG), which tends to mispair with adenine instead of the usual cytosine. This leads to G:C>T:A transversions in the DNA [Isidro et al 2004]. The key steps of DNA base excision repair are carried out by a set of enzymes that work together to prevent mutagenesis by 8-oxo-dG. The enzymes are nucleotide triphosphate NUDT1 (or MTH1) and DNA glycosylases OGG1 and MUTYH. NUDT1 prevents the oxidized G nucleotide from being incorporated during DNA replication by removing 8-oxodGTPs from the nucleotide pool and OGG1 detects and excises 8-oxo-dG adducts that have been misincorporated into the DNA. MUTYH works to excise the misincorporated adenine bases to prevent the G:C>T:A transversion from occurring. After adenine excision, further downstream proteins such as RPA1 repair the mutagenic abasic site [Parker & Eshleman 2003, Isidro et al 2004].MUTYH is expressed in more than ten alternative splice variants encoding at least seven isoforms of the MUTYH protein (429–549 amino acids) [Out et al 2010]: Transcript variant NM_001048171.1 encodes protein isoform 2, NP_001041636.1, with 535 amino acid residues. Transcript variant NM_012222.2 encodes protein isoform 1, NP_036354.1, 546 amino acids. The longest transcript variant NM_001128425.1, encodes protein isoform 5, NP_001121897 with 549 amino acid residues]. The isoforms differ in their N-terminus and the part encoded by exon 3. The N-terminus contains a mitochondrial localization signal (MLS) and putative nuclear localization signals (NLS) are located both at the N-terminus and C-terminus. The functional significance of the MLS and NLS in MUTYH is not entirely clear. The function of the alternative transcripts and isoforms is also unclear. Possibly they possess different glycosylase activity levels and/or have different expression levels in different tissues.Abnormal gene product. A lack of functional MUTYH leads to accumulation of G:C>T:A transversions in daughter DNA strands post-replication. Studies indicate that this transversion is common in colorectal tumor DNA from individuals with MAP. These mutations result in the formation of a stop codon in the mRNA, which then results in a truncated protein product [Lipton & Tomlinson 2004].