Ordering
  • 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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Invitae Colorectal Cancer Guidelines-Based Panel

Test description

The Invitae Colorectal Cancer Guidelines-Based Panel analyzes up to 20 genes associated with a 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.

Individuals with hereditary cancer risk have an elevated chance 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. These measures may prevent cancer or lead to earlier diagnosis, increasing the chances of successful treatment and survival.

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Primary panel (19 genes)

APC AXIN2 BMPR1A CHEK2 EPCAM GREM1 MLH1 MSH2 MSH3 MSH6 MUTYH NTHL1 PMS2 POLD1 POLE PTEN SMAD4 STK11 TP53

Add-on Gene with Emerging Data for Colorectal Cancer (1 gene)

Invitae offers this gene as an add-on to our guidelines-based colorectal panel based on recent clinical updates.

RPS20

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.

  • Lynch syndrome (LS)
  • familial adenomatous polyposis (FAP)
  • attenuated familial adenomatous polyposis (AFAP)
  • MUTYH-associated polyposis (MAP)
  • Peutz-Jeghers syndrome (PJS)
  • juvenile polyposis syndrome (JPS)
  • serrated polyposis syndrome (SPS)
  • Li-Fraumeni syndrome (LFS)
  • Cowden and Cowden-like syndrome (CS)
  • oligodontia-colorectal cancer syndrome
  • constitutional mismatch repair deficiency (CMMR-D)

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%. Up to 5% of heritable colorectal cancer 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 Colorectal Cancer Guidelines-Based Panel tests for other hereditary colorectal cancer syndromes, most of which are also associated with other cancer types. Individuals who have inherited a pathogenic variant in one of these genes have an elevated risk of developing cancer, and many of these cancers may be difficult to detect or treat. Identifying those at high risk may enable additional screening, surveillance, and interventions, which would result in risk reduction and early diagnosis, thereby increasing the chances of successful treatment and survival.

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 may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. 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
AXIN2 elevated (PMID: 21416598, 26025668, 15042511, 23838596)
BMPR1A 38%–68% (PMID: 25645574, 16246179, 17303595) gastric, pancreatic
CHEK2 elevated (PMID: 21807500, 23713947, 23946381, 17164383) breast, thyroid, prostate
EPCAM 75%–82% (PMID: 21145788, 20301390) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
GREM1 elevated (PMID: 26169059, 22561515, 25419707)
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
MSH3 elevated (PMID: 27476653)
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
NTHL1 elevated (PMID: 25938944, 26559593, 26431160, 27720914, 17029639)
PMS2 up to 20% (PMID: 18602922) uterine, ovarian, gastric, pancreatic, duodenal, urinary tract, brain, prostate
POLD1 elevated (PMID: 23263490, 26133394, 25529843)
POLE elevated (PMID: 23263490, 26133394, 25529843)
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

Most of the genes on this panel have autosomal dominant inheritance. Several also have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions, as outlined below:

  • MSH3 is associated with MSH3-associated polyposis
  • NTHL1 is associated with NTHL1-associated polyposis
  • MUTYH is associated with autosomal recessive MUTYH-associated polyposis (MAP)
  • MLH1, MSH2, MSH6, and PMS2 are associated with constitutional mismatch repair deficiency (CMMR-D)

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 assist in identifying individuals who may benefit from consideration of this test, including those with 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)

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  91. Rohlin, A, et al. A mutation in POLE predisposing to a multi-tumour phenotype. Int. J. Oncol. 2014; 45(1):77-81. doi: 10.3892/ijo.2014.2410. PMID: 24788313
  92. 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
  93. Chubb, D, et al. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. J. Clin. Oncol. 2015; 33(5):426-32. doi: 10.1200/JCO.2014.56.5689. PMID: 25559809
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For management recommendations, please refer to:

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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
APC* NM_000038.5
AXIN2 NM_004655.3
BMPR1A* NM_004329.2
CHEK2 NM_007194.3
EPCAM* NM_002354.2
GREM1* NM_013372.6
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH3 NM_002439.4
MSH6 NM_000179.2
MUTYH NM_001128425.1
NTHL1 NM_002528.6
PMS2 NM_000535.5
POLD1* NM_002691.3
POLE NM_006231.3
PTEN NM_000314.4
RPS20 NM_001023.3
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).
POLD1: Sequencing analysis for exons 22 includes only cds +/- 10 bp.
TP53: Deletion/duplication analysis covers the promoter region.