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BMPR1A

Alias

10q23del; ACVRLK3; ALK3; CD292; SKR5

Associated disorders

The BMPR1A gene is associated with autosomal dominant juvenile polyposis syndrome (JPS) (MedGen UID: 87518).

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BMPR1A

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BMPR1A: Deletion/duplication analysis covers the promoter region.


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The BMPR1A gene encodes a bone morphogenetic protein (BMP) receptor, a transmembrane serine/threonine kinase. BMPs repress Wnt-signaling and inappropriate activation of this pathway through loss of BMPR1A function is thought to contribute to cancer progression. BMPR1A has also been shown to play a role in apoptosis, and cell differentiation.

BMPR1A – juvenile polyposis
MedGen UID: 87518

Clinical condition
Juvenile polyposis syndrome (JPS) is a cancer predisposition syndrome that is characterized by the development of numerous hamartomatous polyps in the gastrointestinal tract (stomach, small intestine, colon, and rectum). The number of polyps varies from fewer than five to more than 100. Polyposis typically begins in the mid-teens to late twenties, but can also present in childhood. Individuals with JPS develop polyps at a young age that are most often benign, however, the term “juvenile polyp” refers to a specific histologic type of polyp, not the age at diagnosis (PMID: 22965402; 25394175; ASCO. Cancer.Net: Juvenile Polyposis Syndrome. Accessed February 2018; National Library of Medicine. Genetics Home Reference: Juvenile Polyposis Syndrome. Accessed February 2018). JPS is associated with a 17-22% risk of colorectal cancer by age 35 that approaches 68% by age 60 (PMID: 20301642, 25645574, 17303595, 16246179), a 21% risk of gastric cancer (PMID: 20301642, 20859198, 9869523), and a currently unspecified risk of pancreatic cancer (PMID: 2705469; ASCO. Cancer.Net: Juvenile Polyposis Syndrome. Accessed February 2018. National Library of Medicine). There may also be an increased risk for other cancer types, but the current evidence is preliminary. Associated health complications may include rectal bleeding, abdominal pain, anemia, and obstruction.

Gene information
The bone morphogenetic protein (BMP) receptors are a family of transmembrane serine/threonine kinases (NCBI Gene. Gene ID: 657. Accessed February 2018). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

Inheritance
JPS has autosomal dominant inheritance. This means that an individual with a pathogenic variant in BMPR1A 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. Most cases are inherited from a parent; however, the remainder appear to occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 20301642 ).

Management
To establish the extent of disease and needs in an individual diagnosed with JPS, the following evaluations are recommended (PMID: 20301642; NCCN. Surveillance Guidelines for JPS. Version 3.2017) ):

  • a history for abdominal pain, rectal bleeding, constipation, diarrhea, or change in stool size, shape, or color
  • complete blood count (CBC), colonoscopy, and upper endoscopy at age 15 years or at the time of initial symptoms—whichever is earlier
  • medical genetics consultation

The most effective management for JPS is routine colonoscopy with endoscopic polypectomy. Medical management guidelines for JPS have been established and include the following (PMID: 20301642 NCCN. Surveillance Guidelines for JPS. Version 3.2017 ):

  • Due to the increased risk of colorectal cancer, colonoscopies should be performed every 2–3 years—annually, if polyps are found.
    • If only one or a few polyps are identified, the polyps should be removed. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.
    • If many polyps are identified, removal of most of the colon or stomach may be necessary. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.
  • Due to a 21% risk of stomach cancer, upper endoscopies should be performed every 2–3 years—annually, if polyps are found.
  • No specific screening/surveillance guidelines have been proposed for small intestinal or pancreatic cancer because they appear to be rare.

Early endoscopic polypectomy may reduce morbidity by reducing the risk for cancer, bleeding, or intestinal obstruction. In some cases, removal of all or part of the colon or stomach may be necessary to alleviate symptoms or to reduce cancer risk when a large number of polyps are present.

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 in BMPR1A 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 BMPR1A 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 Surveillance Guidelines for JPS. 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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

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
BMPR1A* NM_004329.2


*BMPR1A: Deletion/duplication analysis covers the promoter region.