• 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




Associated disorders

The GREM1 gene is associated with autosomal dominant hereditary mixed polyposis syndrome (HMPS) in individuals who carry a duplication spanning the 3’ end of the adjacent SCG5 gene and a region upstream of the GREM1 locus (MedGen UID: 430218, PMID: 22561515).

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GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.

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This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. In mouse, this protein has been shown to relay the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge during limb bud outgrowth. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

GREM1—hereditary mixed polyposis syndrome
MedGen UID: 430218

Clinical condition
The GREM1 gene is associated with adult-onset hereditary mixed polyposis syndrome (HMPS), characterized by an increased risk of developing various types of colon polyps that may become malignant (PMID: 22561515). Affected individuals often present with an atypical pattern of polyposis in the colon and rectum. Polyp types associated with HMPS include atypical juvenile, hyperplastic, metaplastic, and adenomas. Adenoma types include flat, tubular, papillary, and serrated. Colorectal carcinoma occurs in a high proportion of reported families; however, the data are currently limited and lifetime risks are not well established (PMID: 25022750). The average age of polyp presentation is 40 years and there are no other clinical features or organ systems associated with this condition (PMID: 23724922).

Gene information
GREM1 encodes a modifier of TGF-Beta/BMP pathways. The TGF-Beta pathway has been shown to be an important contributor of colorectal tumorigenesis. GREM1 is a cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis. It is also a BMP antagonist required for early limb outgrowth and patterning in maintaining the fibroblastic growth factor 4-sonic hedgehog feedback loop (UniProtKB – O60565 (GREM1_HUMAN). Accessed February 2018; PMID: 23724922; OMIM: 603054).

The GREM1 gene is associated with hereditary mixed polyposis syndrome (HMPS) in individuals who carry a duplication spanning the 3’ end of the adjacent SCG5 gene and a region upstream of the GREM1 locus. This variant has no effect on SCG5 gene expression but is associated with greatly increased GREM1 expression (PMID: 22561515). This variant is a founder mutation in the Ashkenazi Jewish population and is currently the only known pathogenic variant involving GREM1. The frequency of this pathogenic duplication in other ethnicities is unknown and it is currently unclear if additional pathogenic variants in GREM1 cause HMPS (PMID: 25992589).

Hereditary mixed polyposis syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant in GREM1 has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in GREM1 has a 50% risk of passing that variant on to offspring.

Medical management and surveillance protocols for individuals with a pathogenic variant in GREM1 have been developed by the National Comprehensive Cancer Network (NCCN) (NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017).

  • Begin colonoscopy at 25-30 years of age
    • If negative, continue colonoscopy every 2-3 years thereafter.
    • If polyps are found, colonoscopy is recommended every 1-2 years with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy.
  • Surgical evaluation, if appropriate.

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding GREM1 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow published screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Additional reference
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed February 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Review date: February 2018

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
GREM1* NM_013372.6

*GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.