Interpretive Handbook

Test 61705 :
Hereditary Colon Cancer Multi-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. The 2 most common hereditary colorectal cancer syndromes are Lynch syndrome and familial adenomatous polyposis (FAP). There are multiple other genes that are also known to cause to hereditary colorectal cancer or contribute to an increased risk for colorectal cancer. This panel uses array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) to evaluate for germline deletions and duplications in 16 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


Familial adenomatous polyposis


Hereditary mixed polyposis syndrome


Peutz-Jeghers syndrome


Juvenile polyposis syndrome


Juvenile polyposis syndrome


PTEN hamartoma tumor syndrome (ie, Cowden syndrome)


Hereditary diffuse gastric cancer


Lynch syndrome


Lynch syndrome


Lynch syndrome


Lynch syndrome


Lynch syndrome


Li-Fraumeni syndrome


Oligodontia-colorectal cancer syndrome


Low-risk gene


Low-risk gene


Note: This test is appropriate for patients who have previously undergone sequence analysis for specific hereditary colorectal cancer-related genes with negative results.


HCCP Hereditary Colon Cancer Multi-Gene Panel 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

Serving as a second-tier test for patients in whom previous targeted gene mutation analyses for specific hereditary colorectal cancer-related genes were negative


Establishing a diagnosis of a hereditary colon cancer syndrome in some cases, allowing for targeted cancer surveillance of associated extra-colonic organs known to be at increased risk for cancer


Identifying mutations within genes known to be associated with increased risk for colon cancer allowing for predictive testing of at-risk family members

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:

Some individuals who have involvement of 1 or more of the genes on the panel may have a mutation that is not identified by the methods performed. The absence of a mutation, therefore, does not eliminate the possibility of a hereditary colorectal cancer syndrome or other heritable risk for colon cancer. For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene mutation in an affected family member.


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.


In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.


A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories at 1-800-533-1710 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