Gene test interpretation: MUTYH

INTRODUCTION — This monograph summarizes the interpretation of germline testing of the MUTYH gene.

It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately [1].

OVERVIEW

How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).

Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).

●Genotype – Identifies the variants in the gene(s) tested. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).

●Interpretation – Determines pathogenicity of the variants identified. (See "MUTYH-associated polyposis", section on 'Genetics'.)

The table provides a glossary of genetic testing terms (table 2).

Classification of variants — It is important to review which gene(s) were analyzed and which variants in those genes were tested, as some tests use comprehensive sequencing whereas others only screen for selected genes and/or selected variants.

The pathogenicity of each variant is classified by the testing laboratory into one of five categories based on information available to them at the time (table 3) [2].

The classification for many variants continues to be updated, especially for variants of uncertain significance (VUS), as more evidence regarding pathogenicity (or lack thereof) becomes available. The uncertainty reflects the current state of information and knowledge available, rather than the accuracy of genotyping or the likelihood of disease.

If there is concern about the classification, such as for a VUS, obtain an updated interpretation periodically (eg, annually). This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a clinical geneticist, genetic counselor, or other specialist (see 'Locating a genetics expert' below and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Locating a genetics expert'); there is no gold standard approach. Some laboratories routinely provide updates and others require a request. Likely benign and benign variants are not reported (or are reported as negative). Many VUSs are reclassified as benign.

Disease associations — MUTYH-associated polyposis (MAP) is an autosomal recessive polyposis syndrome caused by biallelic pathogenic germline variants in the base excision repair gene MUTYH (figure 1 and figure 2). Individuals with MAP may be homozygous or compound heterozygous for pathogenic germline variants in MUTYH. Individuals with MAP are at increased risk for developing gastrointestinal polyps and several types of cancer.

●Colorectal polyps and cancer – Individuals with MAP usually develop up to 100 colorectal adenomatous polyps by the fifth or sixth decade of life and have an increased risk of colorectal cancer. However, the clinical presentation can vary, and biallelic MUTYH pathogenic variants have been identified in individuals with colorectal cancer in the setting of few (<10) or no colorectal polyps. Serrated adenomas and hyperplastic and serrated polyps may also occur.

●Upper gastrointestinal manifestations – Individuals with MAP are at increased risk of developing gastric and duodenal polyps and cancers of the stomach and duodenum.

●Other – Individuals with MAP are at increased risk of the ovaries, bladder, thyroid, and skin. Other rare extracolonic features that have been reported in patients with MAP include osteomas, congenital hypertrophy of the retinal pigment epithelium, dental cysts, desmoid tumors, sebaceous hyperplasia, and Muir-Torre phenotype with sebaceous gland tumors.

INDIVIDUALS WITHOUT CANCER

Implications of a biallelic pathogenic or likely pathogenic variant — We treat all biallelic (homozygous or compound heterozygous) germline variants in the MUTYH gene that are pathogenic or likely pathogenic the same for purposes of counseling and cancer risk reduction, regardless of the initial reason for testing and the family history (algorithm 1 and table 4).

Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for at-risk family members. (See 'At-risk relatives' below and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'At-risk relatives'.)

Counseling may require additional visits or referral to a genetic counselor, clinical geneticist, or oncologist. Acting upon genetic test results is usually not an emergency; the individual can be reassured that management decisions can be deferred until questions have been answered.

Our approach is largely consistent with the National Comprehensive Cancer Network (NCCN), American College of Gastroenterology (ACG), and British Society of Gastroenterology (BSG) recommendations for surveillance and risk reduction [3-5]. The type of cancer and age of onset in a family member may also inform screening (eg, screening at an earlier age if a family member has an earlier age of onset).

The following interventions may be used for cancer risk reduction depending on the patient's age, values, and preferences (algorithm 1 and table 4).

●Colorectal cancer:

•In individuals with MUTYH-associated polyposis (MAP), colonoscopy with polypectomy every 1 to 2 years, starting at 25 to 30 years of age.

•Colectomy in patients with any one of the following:

-Documented or suspected colorectal cancer

-Multiple large/dysplastic polyps and/or significant polyp burden that cannot be effectively managed with colonoscopy and polypectomy

•In patients with a subtotal colectomy with ileorectal anastomosis, sigmoidoscopy is performed six months after surgery and annually thereafter.

●Upper gastrointestinal tract:

•Baseline upper endoscopy for gastric polyps and duodenoscopy for duodenal polyps in patients with MAP at age 30 to 35 years.

•The interval for subsequent screening should be based on the extent of duodenal polyposis. In patients without evidence of duodenal adenomas, a repeat upper endoscopy with duodenoscopy should be performed every four to five years.

•In patients with duodenal adenomas, complete polypectomy or sampling of duodenal polyps should be performed at the time of initial discovery and on each subsequent examination. An abnormal-appearing papilla should be biopsied. The frequency of upper endoscopic surveillance varies based on the severity of duodenal polyposis as classified by the Spigelman score (table 5):

-Stage 0: Every four to five years

-Stage I: Every two to three years

-Stage II: Every one to three years

-Stage III: Every 6 to 12 months

-Stage IV: In the absence of surgery (duodenectomy), every six months

●Thyroid cancer:

•Annual thyroid screening by physical examination and ultrasound.

●Other:

•Screening for other MAP-associated cancers is not routinely recommended. (See 'Disease associations' above and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'FMF genetics and disease associations'.)

Additional details and supporting evidence are discussed separately. (See "MUTYH-associated polyposis", section on 'Management'.)

Considerations in individuals with monoallelic pathogenic variant — Individuals with a monoallelic (heterozygous for single variant) MUTYH pathogenic variant have a small increase in risk for colorectal cancer. These individuals can be managed the same as individuals with a first-degree relative with colorectal cancer, with colonoscopic surveillance every five years, beginning 10 years earlier than the earliest colorectal cancer diagnosis in the kindred or at age 40 years, whichever is earlier (algorithm 1 and table 4).

Implications of a negative test — Negative testing means no pathogenic or likely pathogenic variants were identified. However, some tests only query a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other cancer-predisposition genes.

●If the familial variant in MUTYH is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for MAP-associated cancers, with the caveats outlined above (see 'How to read the report' above and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'How to read the report'). However, it is important to assess family history and other cancer risk factors to provide an individualized risk.

●If a familial variant in MUTYH is not known and results of genetic testing are negative, additional risk factors (genetic or acquired) may be present, and additional testing (for other variants in MUTYH, or with a gene panel that includes other colorectal cancer genes) and/or surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer. (See 'Locating a genetics expert' below and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Locating a genetics expert'.)

Implications of a VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).

New information may become available, and the testing laboratory or other resource should be consulted periodically for updates in the classification (eg, annually).

PATIENTS WITH CANCER — The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary colorectal cancer syndromes may be appropriate.

The presence of a pathogenic or likely pathogenic variant in MUTYH may impact several aspects of management, including the following:

●Additional surveillance and prophylactic measures. (See 'Implications of a biallelic pathogenic or likely pathogenic variant' above and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Implications of a biallelic pathogenic or likely pathogenic variant'.)

●Counseling and testing of family members are also often appropriate. (See 'At-risk relatives' below and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'At-risk relatives'.)

For individuals with a negative test or a variant of uncertain significance (VUS) for whom there are reasons to be concerned about a genetic cause, additional genetic testing may be appropriate. The need for additional testing may be discussed with a genetic counselor, the primary oncologist, or other specialists with expertise in managing hereditary colorectal cancer syndromes. (See 'Locating a genetics expert' below and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Locating a genetics expert'.)

CONSIDERATIONS FOR RELATIVES

Preconception counseling — MUTYH-associated polyposis (MAP) exhibits autosomal recessive inheritance. Children of an individual with MAP (two pathogenic or likely pathogenic MUTYH variants) will be obligate carriers because they will inherit one or the other variant. They could be affected with polyposis if they also inherit a pathogenic variant in MUTYH from the other parent. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition' and 'Implications of a biallelic pathogenic or likely pathogenic variant' above and 'Considerations in individuals with monoallelic pathogenic variant' above and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Heterozygous individuals' and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Implications of a biallelic pathogenic or likely pathogenic variant'.)

At-risk relatives — Individuals who test positive for a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.

●Siblings of the index patient with biallelic germline MUTYH variants have a 25 percent chance of having inherited both MUTYH variants and a 50 percent chance of being heterozygous carriers of a single MUTYH variant if they have the same biological parents. (See 'Considerations in individuals with monoallelic pathogenic variant' above and "Gene test interpretation: MEFV (familial Mediterranean fever gene)", section on 'Heterozygous individuals'.)

●Most of the associated cancers do not develop until adulthood. Testing may be deferred until age 18 to allow for informed consent. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

RESOURCES

UpToDate topics

●MUTYH-associated polyposis (MAP):

•Manifestations, cancer risks, and management – (See "MUTYH-associated polyposis".)

●Genetics:

•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)

•Terminology – (See "Genetics: Glossary of terms".)

•Genetic testing – (See "Genetic testing".)

•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

Locating a genetics expert

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●National Institutes of Health (NIH) Cancer Genetics Services Directory