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Colorectal Cancer Comprehensive Panel

Diseases Targeted:

Hereditary Colorectal Cancer

Overview:

The Colorectal Cancer Comprehensive Panel examines 22 genes associated with an increased risk for hereditary colorectal cancer (colon cancer). This test includes both well-established colorectal cancer susceptibility genes, as well as candidate genes with limited evidence of an association with colorectal cancer.

Who is this test for?

Patients with a personal or family history suggestive of a hereditary colorectal cancer syndrome. Red flags for hereditary colorectal cancer could include onset of cancer prior to the age of 50 years, more than one primary cancer in a single person, and multiple affected people within a family. This test is appropriate for patients with both polyposis and nonpolyposis colorectal cancer. After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients. (If there are specific genes that you do NOT want included, please indicate this on the test requisition form.) This test is designed to detect individuals with a germline pathogenic variant, and is not validated to detect mosaicism below the level of 20%. It should not be ordered on tumor tissue.

What are the potential benefits for my patient?

Patients identified with hereditary colorectal cancer can benefit from increased surveillance and preventative steps to better manage their risk for cancer. Information obtained from candidate gene testing may potentially be helpful in guiding clinical management in the future. Also, if an inherited susceptibility is found, your patient’s family members can be tested to help define their risk. If a pathogenic variant is identified in your patient, close relatives (children, siblings, parents) could have as high as a 50% risk to also be at increased risk. In some cases, screening should begin in childhood.

Order Options

Sequencing (included)
Del/Dup (included)

 

Genes

APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, FAN1, GALNT12, GREM1, MLH1, MLH3, MSH2, MSH6, MUTYH, NTHL1, PMS2, POLD1, POLE, PTEN, SMAD4, STK11, TP53 ( 22 genes )

Coverage:

99% at 50x

Specimen Requirements:

Blood (two 4ml EDTA tubes, lavender top) or Extracted DNA (3ug in EB buffer) or Buccal Swab or Saliva (kits available upon request)

Test Limitations:

Test results and variant interpretation are based on the proper identification of the submitted specimen and use of correct human reference sequences at the queried loci. In very rare instances, errors may result due to mix-up or co-mingling of specimens. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient's phenotype, and negative results do not rule out a genetic cause for the indication for testing. Result interpretation is based on the collected information and Alamut annotation available at the time of reporting. This assay is not designed or validated for the detection of mosaicism. DNA alterations in regulatory regions or deep intronic regions (greater than 20bp from an exon) will not be detected by this test. There are technical limitations on the ability of DNA sequencing to detect small insertions and deletions. Our laboratory uses a sensitive detection algorithm, however these types of alterations are not detected as reliably as single nucleotide variants. Rarely, due to systematic chemical, computational, or human error, DNA variants may be missed. Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the confounding contribution of pseudogene sequences or other highly-homologous sequences, sometimes these may still interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses. Deletion/duplication analysis can identify alterations of genomic regions which are a single exon in size. When novel DNA duplications are identified, it is not possible to discern the genomic location or orientation of the duplicated segment, hence the effect of the duplication cannot be predicted. Where deletions are detected, it is not always possible to determine whether the predicted product will remain in-frame or not. Unless otherwise indicated, in regions that have been sequenced by Sanger, deletion/duplication analysis has not been performed.

Patients with Bone Marrow Transplants:
DNA extracted from cultured fibroblasts should be submitted instead of blood/saliva/buccal samples from individuals who have undergone allogeneic bone marrow transplant and from patients with hematologic malignancy.

Gene Specifics:

Gene Notes
GALNT12 Due to high GC content, copy-number variants located in exon 1 of the GALNT12 gene (NM_024642.4) cannot be reliably detected and will not be reported.
MSH2 Inversion of MSH2 exons 1-7 ("Boland" inversion) is assessed for Lynch Syndrome, Colorectal, Endometrial, and Prostate Cancer Panel testing (for both Focus and Comprehensive Panels) as well as Comprehensive Gastric Cancer Panel testing. Unless otherwise specified, this testing is not performed for other cancer panels, but is available upon request.

CPT Codes:

CPT Code 81436, 81479

NOTE: The CPT codes listed on the website are in accordance with Current Procedural Terminology, a publication of the American Medical Association. CPT codes are provided here for the convenience of our clients. Clients who bill for services should make the final decision on which codes to use.

Gene Descriptions:

Gene Reason Reference
APC Heterozygous pathogenic variants in APC are associated with both classic and attenuated familial adenomatous polyposis (FAP), Gardner syndrome, Turcot syndrome, and Hereditary Desmoid disease. PubMed: 20301519; OMIM: 175100
BMPR1A Heterozygous pathogenic variants in BMPR1A are associated with Juvenile Polyposis Syndrome (JPS). PubMed: 17303595, 20301642, 9869523; OMIM: 174900
CDH1 Pathogenic heterozygous variants in the CDH1 gene are associated with signet ring cell colon cancer, as well as gastric and lobular breast cancer. PubMed: 11729114, 20301318; OMIM: 192090
MSH6 Autosomal dominant pathogenic variants in MSH6 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome. Biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
EPCAM Heterozygous pathogenic variants in the EPCAM gene cause Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome. PubMed: 20301390, 23462293
SMAD4 Heterozygous pathogenic variants in SMAD4 are associated with Juvenile Polyposis Syndrome (JPS). Biallelic pathogenic variants cause Hereditary Hemorrhagic Telangiectasia (HHT). PubMed: 19553198, 20301642
MLH1 While heterozygous pathogenic variants in MLH1 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
MSH2 Heterozygous pathogenic variants in MSH2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome. Biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
MUTYH Biallelic pathogenic variants in the MUTYH gene cause MUTYH-associated polyposis syndrome (MAP). Heterozygous pathogenic variants in the MUTYH gene may result in a small increased risk for colon cancer. PubMed: 16492921, 19394335, 23035301
NTHL1 Biallelic mutations in the base excision repair gene NTHL1 have been associated with familial adenomatous polyposis-3 (FAP3) which is also referred to as NTHL1-associated polyposis (NAP). PubMed: 28331556, 26431160; OMIM: 602656
PMS2 Heterozygous pathogenic variants in PMS2 are associated with Hereditary Nonpolyposis Cancer Syndrome (HNPCC), also known as Lynch syndrome. PMS2 is the least common of the mismatch repair genes that cause HNPCC, accounting for less than 5% of cases. Biallelic pathogenic mutations in PMS2 have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065
POLD1 Heterozygous pathogenic variants in POLD1 have been associated with colorectal cancer and other adenomas including endometrial and breast. PubMed: 24509466, 23263490
POLE Heterozygous pathogenic variants in the POLE gene are associated with early onset colorectal cancer (CRC) and polyposis, also known as Polymerase Proofreading-associated Syndrome (PPAS). Further studies are needed to determine which cancers are directly related to POLE gene variants and the levels of associated risks. Based on the information available today, the risk for colorectal cancer appears to be significantly elevated, and the risk for brain tumors may also be increased . PubMed: 23263490, 26133394; OMIM: 174762
PTEN Individuals with heterozygous pathogenic PTEN variants are at a significantly increased risk for multiple types of cancers, including breast, thyroid, colorectal, endometrial, renal, and others. Autosomal dominant mutations in PTEN have been associated with a spectrum of disorders sometimes referred to as PTEN hamartoma tumor syndrome. PHTS includes several conditions with overlapping clinical features, including Bannayan-Riley-Ruvalcaba syndrome (BRRS), Cowden syndrome (CWS1), macrocephaly/autism syndrome, and PTEN-related Proteus syndrome (PS). PubMed: 20301661; OMIM: 601728
STK11 Autosomal dominant pathogenic variants in STK11 have been associated with Peutz-Jeghers syndrome (PJS) which is associated with an increased risk for multiple types of cancer, including breast, ovarian, gastric, colorectal, and pancreatic. PubMed: 15121768, 20301443; OMIM: 175200, 260350
TP53 Heterozygous pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome, a condition that increases risk for many types of cancer, including colorectal cancer. PubMed: 16401470, 27713038, 20301488, 26014290, 2614290; OMIM: 151623, 191170
AXIN2 Heterozygous pathogenic variants in AXIN2 are associated with Oligodontia-Colorectal Cancer Syndrome (ODCRCS) . ODCRCS is associated with an elevated risk for colorectal (colon) cancer in both men and women, in comparison to the general population, albeit the current elevation in risk remains unkn PubMed: ­­­­­­­­­15042511; OMIM: 608615
CHEK2 Heterozygous pathogenic variants in CHEK2 are associated with approximately a two-fold increased risk for breast cancer, as well as an increased risk for other CHEK2-associated cancers, including colon cancer. PubMed: 15492928, 21807500, 23713947, 28283864
FAN1 Heterozygous pathogenic variants in the FAN1 gene have been associated with Hereditary Non-polyposis Colon Cancer (HNPCC) in a few families. However, additional research is needed to confirm this association. PubMed: 26052075, 27713038
GREM1 Duplications upstream from the GREM1 gene have been associated with Hereditary Mixed Polyposis syndrome. PubMed: 22561515, 25992589, 26947005, 28242209; OMIM: 603054
MLH3 Autosomal dominant pathogenic variants in MLH3 have been found in a few families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Further studies are needed, however, to confirm the association. PubMed: 11586295, 12702580, 20301390; OMIM: 604395
GALNT12 Heterozygous germline pathogenic variants in GLNT12 may contribute to an increased risk for colorectal cancer; however, additional research is needed to confirm this association and define any related risks. PubMed: 19617566, 22461326, 24115450
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