The HOXB13 c.251G>A (p.Gly84Glu) variant is observed more frequently in males with prostate cancer compared to healthy controls (PMID: 22236224, 23064873, 26517352, 26108461, 25629170, 25595936, 24026887).
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HOXB13: Analysis is limited to the NM_006361.5:c.251G>A, p.Gly84Glu variant.
Invitae tests that include this gene:
The HOXB13 gene, which encodes a transcription factor, one of the homeobox protein family, acts as a tumor suppressor and is thought to play a role in the development and maintenance of the skin.
Prostate cancer is one of the most common types of cancer diagnosed in men. Hereditary prostate cancer accounts for approximately 5-10% of all prostate cancer. It is defined by the occurrence of prostate cancer in at least three men in a nuclear family, prostate cancer affecting three generations in a family, or two relatives diagnosed before age 56 (PMID: 26176944).
Numerous studies have shown that the c.251G>A (p.Gly84Glu) variant in HOXB13, also known as G84E, is associated with an increased risk of prostate cancer (PMID: 26176944, 23457453, 22236224, 23064873, 22841674, 26517352, 23518396, 26108461, 25629170, 25595936, 24026887). This variant is associated with earlier-onset diagnosis (<55 years) and individuals with this variant are more likely to have a positive family history of prostate cancer (PMID: 23292082, 22236224, 24026887, 26108461, 25595936, 23396964).
Large case control studies and meta-analysis across studies demonstrated that men with this variant have approximately a 33-60% lifetime risk of prostate cancer compared to the general population risk of 12% (PMID: 22841674, 23457453, 25595936, 26517352, 24026887). Additionally, this variant is present in 0.2% of the general population (Exome Aggregation Consortium (ExAC). Accessed September 2016). The G84E variant is observed at a higher frequency in individuals of European ancestry (0.8%), suggesting it may be a European founder mutation (PMID: 22841674). An individual with this variant will not necessarily develop cancer in his lifetime, but the risk is increased over the general population risk. There may also be an increased risk for other cancer types, however, the current evidence is limited and conflicting (PMID: 22853031, 23099437, 23292082, 25629170, 26517352).
HOXB13 is a tumor suppressor gene that encodes a transcription factor that is part of the homeobox protein family ( National Library of Medicine. Genetics Home Reference. HOXB13. Accessed September 2016). HOXB13 plays a role in embryonic growth and development, and is particularly expressed in the prostate, where it interacts with androgen receptors (PMID: 25629170, 22236224).
Hereditary predisposition to cancer due to the HOXB13 G84E variant has autosomal dominant inheritance. This means that an individual with this variant has a 50% chance of passing it to their offspring. Once such a variant is detected, it is possible to identify at-risk relatives who can pursue testing. 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).
The National Comprehensive Cancer Network® (NCCN) currently does not recommend additional prostate cancer screening for individuals with the HOXB13 G84E variant beyond what is recommended for the general population. However, NCCN cautions that cancer screening should ultimately be guided by personal and family history (The National Comprehensive Cancer Network® (NCCN). Prostate Cancer Early Detection. Version 1. 2016). In the absence of formal guidelines, a formal urology consultation may be considered.
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.
Even though data regarding HOXB13 is limited, knowing if the G84E 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 HOXB13 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 standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Review date: September 2016
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.
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|
*HOXB13: Analysis is limited to the NM_006361.5:c.251G>A, p.Gly84Glu variant.