• 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 CDC73 gene is associated with autosomal dominant hyperparathyroidism-jaw tumor syndrome (HPT-JT), parathyroid carcinoma, and familial isolated hyperparathyroidism (FIH) (MedGen UID: 310065, 146361, 333554), collectively referred to as CDC73-related conditions.

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The CDC73 gene encodes parafibromin, which is thought to be involved in the regulation of gene transcription, along with cell growth and proliferation. The CDC73 gene also appears to be involved with the organization of the cytoskeleton in cells.

CDC73-related disorders
MedGen UID: 146361

Clinical condition
CDC73-related conditions include familial isolated hyperparathyroidism (FIHP), parathyroid carcinoma, and hyperparathyroidism-jaw tumor (HPT-JT) syndrome (PMID: 23293331, 23029104, 12434154). FIHP and hereditary parathyroid carcinoma lack additional extra-organ involvement, but HPT-JT is typically a multi-systemic neoplastic condition. Features include:

  • primary hyperparathyroidism due to parathyroid adenoma or carcinoma
  • ossifying fibroma(s) of the maxilla and/or mandible
  • renal lesions including cysts, hamartomas, and possibly Wilms tumor

Not everyone with a CDC73 pathogenic variant will manifest symptoms, but up to 90% will develop a CDC73-related condition. In HPT-JT, the onset of primary hyperparathyroidism (PHPT) typically occurs in adolescence or early adulthood; 80% of cases will develop PHPT by age 40 (PMID: 20301744).

  • The risk of parathyroid carcinoma is 10–15%.
  • Approximately 20% of affected individuals develop renal cysts, hamartomas, and possibly Wilms tumor; however, the lifetime risk of kidney cancer is currently unclear.
  • The risks of ossifying jaw fibromas is 30–40%.

It has been suggested that CDC73-related disorders be considered as part of a single spectrum. Supportive evidence includes the highly variable expression of symptoms observed in individuals with CDC73 pathogenic variants and that all three conditions are caused by the same gene (PMID: 24678936, 25959515, 24402736, 25511968).

There is preliminary evidence to suggest HPT-JT may be associated with benign and malignant uterine tumors, however, the available data are insufficient to make a clear determination regarding this association. Therefore, CDC73 is considered a “preliminary evidence gene” in its association with uterine cancer by Invitae (PMID: 15606373, 20301744). preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary evidence genes.

Gene information
CDC73 is a tumor-suppressor gene, meaning its function is to help control rate of growth and cell division in the body. This gene is likely involved in transcriptional and post-transcriptional control pathways and may be involved in cell-cycle progression ( UniProt consortium, UniProtKB – Q6P1J9 (CDC73_HUMAN); http://www.uniprot.org/uniprot/Q6P1J9. Accessed September 2015). 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.

Hereditary predisposition to cancer due to pathogenic variants in the CDC73 gene 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. 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).

There are no established screening or surveillance guidelines for individuals with a pathogenic CDC73 variant, but the following have been suggested to establish the extent of disease in an individual diagnosed with a CDC73-related disorder (PMID: 20301744):

  • evaluation for primary hyperparathyroidism: measurement of intact parathyroid hormone and serum calcium concentration
  • baseline bone density of the lumbar spine, hips, and distal radius by dual-energy x-ray absorptiometry (DXA) and 24-hour urine collection for calcium in individuals with evidence of primary hyperparathyroidism
  • evaluation for jaw tumors: panoramic jaw x-ray with neck shielding
  • evaluation for renal lesions: renal ultrasound examination preferred; CT and/or MRI as clinically indicated
  • evaluation for uterine tumors in women starting at reproductive age: pelvic examination as part of routine gynecologic care; pelvic ultrasound examination (preferred) and other imaging studies (CT and/or MRI) as clinically indicated

The following surveillance guidelines have been proposed (PMID: 20301744):

  • Measure serum concentrations of calcium, iPTH, and 25-(OH) vitamin D (to evaluate for possible coexisting vitamin D deficiency as a cause of elevated iPTH levels or unexpectedly “normal” calcium concentrations) every 12 months, starting between ages 5 and 10 years.
  • In patients with a history of parathyroid carcinoma who develop a rise in calcium levels, consider the possibility of a new primary parathyroid tumor in addition to recurrence/progression of malignant disease.
  • Consider periodic parathyroid ultrasound examination for the detection of non-functioning parathyroid carcinoma, which has developed on rare occasion.
  • Obtain panoramic x-ray dental imaging with neck shielding at least every five years. Dental providers should be notified of the presence of a CDC73-related disorder and the need for monitoring for osseous fibromas of the maxilla and mandible.
  • Monitor for kidney lesions by renal ultrasound examination at least every five years, starting at the age of diagnosis.
    • Serum creatinine concentrations should be monitored in those individuals with renal cysts.
    • Individuals with solid lesions should be referred for appropriate subspecialty care.
  • Starting at reproductive age, women with a CDC73-related disorder should undergo regular gynecologic care (including pelvic examination).
    • Care providers in obstetrics and gynecology should be notified of the risk of uterine tumors
    • Pelvic ultrasound examination should be obtained for any woman with a menstrual disorder (particularly abnormal uterine bleeding or menorrhagia), with further imaging studies (CT or MRI) as clinically indicated.

In addition, it is recommended that individuals with CDC73-related conditions avoid dehydration, radiation exposure, and biopsy of extra-thyroid neck tissue, which may increase the risk of seeding a possible parathyroid carcinoma (PMID: 20301744):

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 the data regarding CDC73 are limited, 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 CDC73 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 consider implementing proposed 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 2015

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
CDC73 NM_024529.4