C15DUPq; CKTSF1B1; CRAC1; CRCS4; DAND2; DRM; DUP15q; GREMLIN; HMPS; HMPS1; IHG-2; MPSH; PIG2
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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The GREM1 gene encodes a modifier of TGF-Beta/BMP pathways, and the TGF-Beta pathway has been shown to be an important contributor of colorectal tumorigenesis.
GREM1—hereditary mixed polyposis syndrome
MedGen UID: 430218
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 ).
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 2017 ; 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 2.2016 ).
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.
Review date: February 2017
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|
*GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.