• 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



OSRC; PPP1R130; RB; p105-Rb; pRb; pp110

Associated disorders

The RB1 gene is associated with autosomal dominant retinoblastoma (MedGen UID: 20552). Additionally, evidence of varying degrees suggests a possible association between the RB1 gene and several cancer types in retinoblastoma survivors (PMID: 14996857, 22355046).

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The RB1 gene encodes retinoblastoma 1, a tumor suppressor that regulates DNA replication and cell growth. The RB1 protein also interacts with other proteins to control cell survival, differentiation and apoptosis.

RB1 Hereditary retinoblastoma
MedGen UID: 20552

Clinical condition
Retinoblastoma (Rb) is a rare, early childhood cancer that forms in the retina of the eye. Most cases are sporadic, unilateral, and diagnosed before 5 years of age. However, 40% of cases are due to an inherited pathogenic variant in the RB1 gene. Retinomas, benign lesions with potential to develop into retinoblastoma, may be detected upon examination (PMID: 20301625, 18211953). Pinealoblastoma is the most well-known brain tumor associated with retinoblastoma, found in 5%–15% of hereditary cases (PMID: 20413604, 10561222, 15269048). Other cancers including osteosarcoma, soft tissue sarcomas, and melanoma have been reported. These typically present in adolescence and adulthood (Genetics Home Reference. Retinoblastoma. Accessed July 2016, PMID: 20301625).

The average age at diagnosis of hereditary Rb is approximately 15 months of age. Roughly 10% of Rb cases have a positive family history. When at-risk individuals undergo aggressive and early screening through serial retinal examinations, tumors are often identified shortly after birth. Nearly everyone with hereditary Rb will develop Rb; however, a small subset of families, approximately 10% of all cases, have approximately a 25% risk of developing Rb and it is more often unilateral (Genetics Home Reference. Retinoblastoma. Accessed July 2016, PMID: 20301625, 8304343). It has been suggested that this lower penetrance may be influenced by specific variant characteristics and parent of origin effects (PMID: 12016586).

Individuals with hereditary Rb have an increased risk for other specific extraocular primary neoplasms (collectively called second primary tumors). The most common second primary tumors include osteosarcomas, soft tissue sarcomas (leiomyosarcomas and rhabdomyosarcomas), and melanomas that typically manifest in adolescence or adulthood (PMID: 20301625). The chance of developing secondary primary cancers in patients with hereditary Rb increases to over 50% in those who have been treated with external beam radiation therapy; however, even survivors not exposed to high-dose radiotherapy still appear to have an increased lifetime risk of developing a late-onset cancer. Specific lifetime risks for these cancers is currently unclear (Genetics Home Reference. Retinoblastoma. Accessed July 2016, PMID: 20301625).

Gene information
The RB1 gene is a key regulator of entry into cell division that acts as a tumor suppressor. RB1 acts as a transcription repressor leading to cell cycle arrest (UniProtKB – P06400 (RB_HUMAN), Accessed July 2016). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers. ally functioning, there may be an increased risk to develop certain types of cancers.

Hereditary Rb has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Most cases are the result of a spontaneous de novo mutation, meaning that an individual with a pathogenic variant has parents who do not have it (PMID: 20301625). However, that individual has a 50% risk of passing it on to offspring.

It is suggested that individuals with a pathogenic variant in RB1, along with their at-risk relatives, have regular clinical monitoring by a physician or medical team with expertise in the treatment of hereditary Rb. Early detection and treatment have been shown to increase ocular retention and preserve vision (PMID: 18197032). Detailed clinical management and surveillance guidelines for individuals with a pathogenic variant in RB1 have been established (PMID: 20237571, 20301625) and include:

  • complete physical examination
  • ophthalmologic examination under anesthesia
  • ocular ultrasonography and/or MRI of head and orbits to confirm and assess the extent of disease
  • brain MRI to evaluate for pinealoblastoma

Affected individuals require frequent follow-up examination for early detection of newly arising intraocular tumors (PMID: 20237571, 20301625):

  • ophthalmoscopic examinations under anesthesia every three to four weeks until age six months, then less frequently until age three years.
    • exams under anesthesia allows for complete visualization of the retina.
    • the risk of anesthesia should be balanced by the benefit of early diagnosis and improved ocular survival (PMID: 14654593).
  • clinical examinations without anesthesia in cooperative children every three to six months until age seven years of age, then annually, and eventually biannually for life.
  • retinomas should be followed with retinal examinations and imaging every one to two years to detect any changes early.
  • because of the high risk for second cancers including sarcomas, melanoma, and other cancers, prompt investigation of any signs or symptoms is indicated; however, effective screening protocols have not yet been developed.
  • brain MRI every 6 months until 5 years of age has been proposed by Rao et al. to screen for pinealoblastoma (PMID: 18197032).

It has been suggested that cancer risks in survivors of hereditary Rb may be reduced by limiting exposure to DNA-damaging agents such as radiotherapy, tobacco, and ultraviolet light (PMID: 14996857).

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, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if an RB1 pathogenic variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant RB1 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Review date: August 2016

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
RB1 NM_000321.2