Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.0.1
• GENE/GENE PANEL: MUTYH (MYH)
• Condition: MYH-Associated Polyposis
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• MUTYH (MYH) ⇔ 608456: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Colorectal cancer / Regular colonoscopy/polypectomy	2	3C	3B	2	10CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Approximately 4.8% of men and women will be diagnosed with CRC in their lifetime. There are an estimated 1.1 million people currently living with CRC in the United States.
MAP is estimated to account for <1% of all CRC cases, and up to 2% of familial or early-onset CRC cohorts. The exact number of CRC cases due to MAP is unknown, but expected to be small. [1, 2, 3]

Clinical Features

MAP predisposes individuals to an attenuated polyposis phenotype and CRC. Most individuals with MAP have 10 to a few hundred polyps in the colon, although some might have over 1,000. Polyps can be exclusively adenomatous, hyperplastic, or mixed (adenomatous and hyperplastic).

Duodenal polyps and duodenal cancer are common, as well as extraintestinal manifestations including ovarian cancer, bladder cancer, breast cancer, endometrial cancer, skin tumors, and thyroid cancer. [2]

Natural History

Colorectal adenomatous polyps present, on average, at age 50.

In the absence of timely surveillance, the lifetime risk for CRC ranges from 40% to almost 100%.

Duodenal polyps are found in 4-25% of individuals with MAP; the lifetime risk for duodenal cancer in individuals with MAP is 4-5%. [2, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

Genetic counseling, management by physicians or centers with expertise in MAP, and surgical evaluation and counseling are recommended. (Tier 2) [6]

(Procto)Colectomy with IRA or IPAA is recommended for patients with significant polyposis not manageable by polypectomy. (Tier 2) [6, 4, 7]

A baseline thyroid examination is recommended at the time of diagnosis. (Tier 3) [2]

Surveillance

Colonoscopy and polypectomy every 1-2 years, starting in early adulthood (age varies by guideline); polyp burden may warrant earlier surveillance. Although indirect evidence suggests colonoscopic surveillance and polypectomy may be effective in colorectal cancer control, this has yet to be definitively determined. There is no literature to date of any control subjects with bi-allelic MUTYH mutations who have reached the age of 55 years without developing colorectal cancer or polyposis. (Tier 2) [6, 4, 7, 5, 8]

While the efficacy of a surveillance program has not been proven prospectively, regular endoscopic surveillance of the duodenum is advised in literature. It would seem logical to follow the duodenal surveillance schedule for FAP. (Tier 1) [4]

An annual physical exam is recommended. (Tier 2) [6]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Adult context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

It is estimated that 1-2% of the general northern European population is heterozygous for a MUTYH mutation. The prevalence of biallelic carriers of MUTYH mutations can be derived as 1:40,000-1:10,000. (Tier 3) [1, 2, 5]

Penetrance

Penetrance of any clinical feature is nearly 100%, though the penetrance of colorectal polyposis is unknown. (Tier 3) [2]

Penetrance of any clinical feature is nearly 100%, though the penetrance of colorectal polyposis is unknown. Penetrance of CRC in proven biallelic mutation carriers is 80-90%. (Tier 3) [2, 5]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

Development of colorectal adenomas is variable. (Tier 3) [6, 4, 7]

4. What is the Nature of the Intervention?

Nature of Intervention

Endoscopic surveillance can be burdensome for individuals.
There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death. [4, 5]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Surveillance recommendations for MAP begin at an earlier age than the general population screening recommendations. (Tier 2) [6, 4, 7, 5, 8]

Date of Search: 05.16.2014

Reference List

1. Aretz S, Genuardi M, Hes FJ. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP) - update 2012. Eur J Hum Genet. (2013) 21(1).

2. M Nielsen, H Lynch, E Infante, R Brand. MUTYH-Associated Polyposis. 2012 Oct 04 [Updated 2015 Sep 24]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK107219

3. National Cancer Institute. SEER Stat Fact Sheets: Colon and Rectum Cancer. (2014) Website: http://seer.cancer.gov/statfacts/html/colorect.html

4. Association of Comprehensive Cancer Centres. Hereditary colorectal cancer. Amsterdam, The Netherlands Association of Comprehensive Cancer Centres. Other. (2009) Website: https://www.guidelinecentral.com/summaries/hereditary-colorectal-cancer/

5. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, Eaden JA, Rutter MD, Atkin WP, Saunders BP, Lucassen A, Jenkins P, Fairclough PD, Woodhouse CR. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. (2010) 59(5):666-89.

6. National Comprehensive Cancer Network,. Genetic/Familial High-Risk Assessment: Colorectal (version 3.2017). Other. (2017) Website: http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf

7. Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Jarvinen H, Mecklin JP, Moller P, Myrhoi T, Nagengast FM, Parc Y, Phillips R, Clark SK, de Leon MP, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen J. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. (2008) 57(5):704-13.

8. Diagnosis and Management of Colorectal Cancer. SIGN. (2015) Website: http://www.sign.ac.uk/pdf/sign126.pdf