Interpretive Handbook

Test 61704 :
Single-Gene Large Deletion and Duplication Analysis

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Colorectal cancer occurs in approximately 5% to 6% of individuals in the general population. In rare cases, individuals with a family history of colorectal cancer may be at increased risk for colon and other cancers due to a single-gene predisposition syndrome, known as hereditary colorectal cancer. This panel uses array comparative genomic hybridization (aCGH) to evaluate for a previously identified germline deletion or duplication in genes known to be associated with an increased risk for colon cancer development. Two of the genes listed, CHEK2 and MLH3, are not associated with a known hereditary cancer syndrome defined by a distinct spectrum of tumors. However, literature suggests that mutations in these genes may confer an increased risk for colon cancer and, therefore, are predicted to contribute to cancer risk in patients and families.



Known Association


Hereditary mixed polyposis syndrome


Peutz-Jeghers syndrome


Juvenile polyposis syndrome


Juvenile polyposis syndrome


PTEN Hamartoma tumor syndrome (ie, Cowden syndrome)


Hereditary diffuse gastric cancer


Li-Fraumeni syndrome


Oligodontia-colorectal cancer syndrome


Low-risk gene


Low-risk gene


This test is appropriate for diagnostic or predictive testing when a large deletion or duplication in 1 of the listed genes has been identified in a family member, or for patients who have previously undergone sequence analysis for 1 of the listed genes with negative results. Additionally, if family members have had a large deletion or duplication detected by aCGH in MLH1, MSH2, MSH6, EPCAM, or APC, this test may also be ordered.


Note: This test should be ordered if aCGH is desired for a gene listed in the method. Documentation of the gene selected is required. If testing for all of the listed genes is desired, order HCCD / Hereditary Colon Cancer Multigene Large Deletion and Duplication Analysis.


Alternatively, HCCP / Hereditary Colon Cancer Multigene Panel includes next-generation sequencing in addition to aCGH for several genes known to be associated with hereditary colon cancer and may be more appropriate for patients with other indications, including:

-Patients in whom no specific colorectal cancer syndrome is evident but for whom there is a clear familial component

-Patients whose family history is consistent with familial colorectal cancer type X(1)

-Patients with a strong suspicion for a single-gene hereditary colon cancer syndrome based on an autosomal dominant pattern of colon cancer in the family

-Patients with a personal or family history of colonic polyposis

Useful For Suggests clinical disorders or settings where the test may be helpful

Diagnostic or predictive testing for hereditary colorectal cancer when a large deletion or duplication in 1 of the listed genes has been identified in a family member

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(2) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, contact Mayo Medical Laboratories at 800-533-1710 to discuss testing options.


Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.


Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified.


Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.  


Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.


Reclassification of Variants-Policy:

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Lindor NM, Rabe K, Petersen GM, et al: Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005;293(16):1979-1985

2. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300

3. Lindor NM, McMaster ML, Lindor CJ, et al: Concise Handbook of Familial Cancer Susceptibility Syndromes. Second edition. J Natl Cancer Inst Monogr 2008;(38):1-93

4. Genetics of Colorectal Cancer. Edited by JD Potter, NM Lindor. 2009, New York, Springer Verlag, 2009, pp 213-217

5. Jaeger E, Leedham S, Lewis A, et al: Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet 2012;44(6):699-703

6. Ligtenberg MJL, Kuiper RP, Chan TL, et al: Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet 2009;41(1):112-117

7. Lammi L, Arte S, Somer M, et al: Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004;74:1043-1050

8. Liu HX, Zhou XL, Liu T, et al: The role of hMLH3 in familial colorectal cancer. Cancer Res 2003;63(8):1894-1899