Invitae Colorectal Cancer Guidelines-Based Panel

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  • Test code: 01252
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Test description

The Invitae Colon Cancer Guidelines Based Panel analyzes up to 18 genes, variants in which cause significantly elevated risk of hereditary colorectal cancer. These genes were curated based on published best practice guidelines for evaluation of hereditary colorectal cancer (CRC) risk. The genes included in this panel are medically actionable and have published, evidence-based management and risk-reduction options.

Patients with hereditary cancer risk have high risk of developing cancer and require specialized—often intensive—management. This test will help guide cancer screening and risk-reduction measures for colorectal cancer, including defining the age at which screening is initiated, the interval between screening tests, the methodology used, preventive options including surgery, and the risk for subsequent primary cancers in the patient and their family. These measures may prevent cancer or lead to earlier diagnosis, increasing the chances of successful treatment and survival.

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Primary panel (12 genes)

APC BMPR1A EPCAM MLH1 MSH2 MSH6 MUTYH PMS2 PTEN SMAD4 STK11 TP53

Add-on Guidelines Genes with Emerging Data for Colorectal Cancer (6 genes)

Invitae offers these five genes as add-ons to our guidelines-based colorectal panel based on recent clinical updates.

BLM CHEK2 GALNT12 GREM1 POLD1 POLE

Alternative tests to consider

These genes can also be ordered as part of broader multi-gene panels. Depending on the individual’s clinical and family history, a broader panel may be appropriate. Any of these broader panels can be ordered at no additional charge.

  • Cowden and Cowden-like syndrome
  • familial adenomatosis polyposis (FAP)
    • attenuated familial adenomatous polyposis (AFAP)
  • juvenile polyposis syndrome (JPS)
  • Li-Fraumeni syndrome (LFS)
  • Lynch syndrome – also known as hereditary non-polyposis colorectal cancer (HNPCC)
  • MUTYH-associated polyposis (MAP)
  • Peutz-Jeghers syndrome (PJS)
  • serrated polyposis syndrome (SPS)

Colorectal cancer (CRC) is a malignancy of the large intestine (colon) or rectum. Hereditary colon cancer syndromes are generally divided into two types: Lynch syndrome and polyposis syndromes. Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), is caused by pathogenic variants in EPCAM, MLH1, MSH2, MSH6, and PMS2. This condition is the most common inherited cause of colorectal cancer. Polyposis syndromes are characterized by the development of numerous precancerous polyps that may become malignant.

Colorectal cancer is the third-most-common cancer diagnosis in the United States, with a general population risk of 4.8%. Although most cases are sporadic and not inherited, approximately 5%–10% are due to an identifiable gene change, which is called a pathogenic variant. Up to 5% of heritable cases are due to Lynch syndrome, less than 1% are due to familial adenomatous polyposis (FAP), and less than 0.1% are due to hamartomatous polyposis syndromes, including juvenile polyposis syndrome (JPS), MUTYH-associated polyposis (MAP), and Peutz-Jeghers syndrome (PJS).

In addition to these conditions, the Invitae Colon Cancer Guidelines Based Panel tests for other hereditary cancer syndromes with significant risks for colorectal cancer, most of which are also associated with risks for other types of cancer. Guidelines are available for the screening and management of individuals with pathogenic variants in each of these genes.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant can present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant. For gene-associated cancer risks, see the table below.

GeneColorectal cancer riskOther associated cancers
APC 70%–100%  (PMID: 18063416, 19822006, 1673441) sarcoma, duodenal, brain, thyroid, hepatoblastoma, upper stomach
BLM* unknown (PMID: 12242432, 26358404, 12702560, 18210922) various cancers associated with Bloom syndrome (recessive condition)
BMPR1A 38%–68% (PMID: 25645574, 16246179, 17303595) gastric, pancreatic
CHEK2* elevated (PMID: 21807500, 23713947, 23946381, 17164383) breast, prostate, thyroid
EPCAM 75%–82% (PMID: 21145788, 20301390) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
GALNT12* unknown (PMID: 19617566, 22461326) none known
GREM1* elevated (PMID: 26169059, 22561515, 25419707) none known
MLH1 up to 82% (PMID: 20301390, 25070057) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MSH2 up to 82% (PMID: 20301390, 25070057) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MSH6 ♂: up to 44% ♀: up to 20% (PMID: 20028993) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
MUTYH 43%–100% (PMID: 23035301, 19620482) duodenal
PMS2 up to 20% (PMID: 18602922) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
POLD1* elevated (PMID: 23263490, 26133394, 25529843) unknown
POLE* elevated (PMID: 23263490, 26133394, 25529843) unknown
PTEN 9% (PMID: 22252256) breast, uterine, renal, thyroid, brain, skin
SMAD4 38%–68% (PMID: 25645574, 16246179, 17303595) gastric, pancreatic
STK11 39% (PMID: 20051941) breast, ovarian, uterine, gastric, pancreatic, duodenal, lung
TP53 elevated (PMID: 16401470) breast, ovarian, uterine, gastric, pancreatic, sarcoma, brain, lung, adrenal, leukemia

*Guidelines genes with emerging data

Most of the genes on this panel have autosomal dominant inheritance for hereditary colorectal cancer. MUTYH is associated with autosomal recessive MUTYH-associated polyposis (MAP). Several of these genes also result in clinically distinct autosomal recessive conditions, as outlined below:

  • MLH1, MSH2, MSH6, and PMS2 are associated with constitutional mismatch repair deficiency (CMMR-D)
  • EPCAM is associated with congenital tufting enteropathy (CTE)

Colorectal cancer occurs in approximately 1 in 22 individuals in the general population. Up to 5% of all colon cancer cases are attributed to Lynch syndrome.

APC-associated polyposis conditions historically accounted for approximately 0.5% of all colon cancer, but this number is decreasing with greater awareness, early detection, and intervention. Collectively, the APC-associated polyposis conditions have a prevalence of approximately 2-3 in 100,000 individuals.

Approximately 1%-2% of individuals of northern European ancestry are carriers of a MUTYH variant. The prevalence of MAP in this population is estimated at 1 in 20,000 to 1 in 40,000. It is difficult to determine the prevalence of this condition in other ethnicities because the carrier frequency can vary significantly.

Practice guidelines define patients who may benefit from consideration of this test, including patients who have a personal or family history of:

  • colorectal or endometrial cancer diagnosed before age 50
  • multiple primary colorectal tumors
  • tumors of the colorectum, uterus, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands, and keratoacanthomas in three or more relatives
  • greater than 10 colorectal adenomas
  • desmoid tumors, cribriform morular variant of papillary thyroid cancer, multiple extraintestinal gastrointestinal adenomas, or hepatoblastoma
  • gastrointestinal ganglioneuromas or polyps of the hamartomatous, juvenile, ganglio, or serrated type
  • abnormal tumor pathology suggestive of a mismatch repair defect (MSI, IHC, Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern)

  1. Balmaña, J, et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann. Oncol. 2013; 24 Suppl 6:vi73-80. PMID: 23813931
  2. Baris, HN, et al. Prevalence of breast and colorectal cancer in Ashkenazi Jewish carriers of Fanconi anemia and Bloom syndrome. Isr. Med. Assoc. J. 2007; 9(12):847-50. PMID: 18210922
  3. Bellido, F, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet. Med. 2015; :None. doi: 10.1038/gim.2015.75. PMID: 26133394
  4. Clarke, E, et al. Inherited deleterious variants in GALNT12 are associated with CRC susceptibility. Hum. Mutat. 2012; 33(7):1056-8. PMID: 22461326
  5. Cleary, SP, et al. Heterozygosity for the BLM(Ash) mutation and cancer risk. Cancer Res. 2003; 63(8):1769-71. PMID: 12702560
  6. Davis, H, et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat. Med. 2015; 21(1):62-70. doi: 10.1038/nm.3750. PMID: 25419707
  7. Giardiello, FM, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014; 147(2):502-26. PMID: 25043945
  8. Gruber, SB, et al. BLM heterozygosity and the risk of colorectal cancer. Science. 2002; 297(5589):2013. PMID: 12242432
  9. Guda, K, et al. Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc. Natl. Acad. Sci. U.S.A. 2009; 106(31):12921-5. doi: 10.1073/pnas.0901454106. PMID: 19617566
  10. Han, FF, et al. The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA Cell Biol. 2013; 32(6):329-35. doi: 10.1089/dna.2013.1970. PMID: 23713947
  11. Jaeger, E, 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. doi: 10.1038/ng.2263. PMID: 22561515
  12. Kohlmann, W, Gruber, SB. Lynch Syndrome. 2004 Feb 05. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1211/ PMID: 20301390
  13. Ma, X, et al. Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Gut. 2014; 63(2):326-36. doi: 10.1136/gutjnl-2012-304121. PMID: 23946381
  14. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Colorectal. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed September 2015.
  15. Palles, C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 2013; 45(2):136-44. PMID: 23263490
  16. Spier, I, et al. Frequency and phenotypic spectrum of germline mutations in POLE and seven other polymerase genes in 266 patients with colorectal adenomas and carcinomas. Int. J. Cancer. 2015; 137(2):320-31. PMID: 25529843
  17. Stoffel, EM, et al. Hereditary colorectal cancer syndromes: american society of clinical oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European society for medical oncology clinical practice guidelines. J. Clin. Oncol. 2015; 33(2):209-17. PMID: 25452455
  18. Syngal, S, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 2015; 110(2):223-62; quiz 263. doi: 10.1038/ajg.2014.435. PMID: 25645574
  19. Thompson, D, et al. A multicenter study of cancer incidence in CHEK2 1100delC mutation carriers. Cancer Epidemiol. Biomarkers Prev. 2006; 15(12):2542-5. PMID: 17164383
  20. Tomlinson, I. Annals Express: The Mendelian colorectal cancer syndromes. Ann. Clin. Biochem. 2015. PMID: 26169059
  21. Xiang, HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur. J. Cancer. 2011; 47(17):2546-51. PMID: 21807500
  22. de, Voer, RM, et al. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer. Sci Rep. 2015; 5:14060. PMID: 26358404

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
APC* NM_000038.5
BLM NM_000057.3
BMPR1A* NM_004329.2
CHEK2 NM_007194.3
EPCAM* NM_002354.2
GALNT12 NM_024642.4
GREM1* NM_013372.6
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
MUTYH NM_001128425.1
PMS2 NM_000535.5
POLD1 NM_002691.3
POLE NM_006231.3
PTEN* NM_000314.4
SMAD4 NM_005359.5
STK11 NM_000455.4
TP53* NM_000546.5

APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
BMPR1A: Deletion/duplication analysis covers the promoter region.
EPCAM: Analysis is limited to deletion/duplication analysis
GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
PTEN: Deletion/duplication analysis covers the promoter region.
TP53: Deletion/duplication analysis covers the promoter region.