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  • Test code: 01303
  • 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
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Invitae Hyperparathyroidism Panel

Test description

The Invitae Hyperparathyroidism Panel analyzes genes associated with hereditary hyperparathyroidism (HPT). These genes were curated based on the available evidence to date and provide Invitae’s most comprehensive test for individuals and families with features of HPT.

Individuals with a pathogenic variant in one of these genes have a higher risk of developing parathyroid disease—a disease that can be difficult both to detect and to treat. Prolonged parathyroid disease can also cause other health issues that may result in serious complications. It can be extremely helpful to identify those who are at high risk so that additional screening, surveillance and interventions can be initiated—both for parathyroid disease and for other health issues, including certain cancers. These efforts can result in risk-reduction and early diagnosis, which may increase the chances of successful treatment and survival. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (7 genes)

AP2S1 CASR CDC73 CDKN1B GNA11 MEN1 RET

  • autosomal dominant hypocalcemia (ADH)
  • CASR-related disorders
  • CDC73-related disorders
  • CDKN1B-related disorders
  • familial hypocalciuric hypercalcaemia (FHH)
  • hyperparathyroidism jaw tumor syndrome
  • MEN1-related disorders
  • multiple endocrine neoplasia type 1 (MEN1)
  • multiple endocrine neoplasia type 2A (MEN2A)
  • multiple endocrine neoplasia type 2B (MEN2B)
  • multiple endocrine neoplasia type 4 (MEN4)

In the United States, approximately 100,000 people develop hyperparathyroidism (HPT) each year. HPT is twice as common in women than in men, and the risk increases with age. Approximately 1 in 500 women over age 60 will develop HPT. Approximately 5% of HPT cases are familial (inherited). It is unknown if hyperparathyroidism and parathyroid adenomas may predispose to cancer.

The genes on this panel are associated with hereditary predisposition to developing HPT, but the overall percentage of hereditary cases caused by these risk factors is currently unclear. Inclusion of multiple HPT-related genes is expected to increase the clinical sensitivity of this test.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated cancer risks, see the table below.

GeneConditionHPT riskTumor riskOther associated cancers/features
AP2S1 Familial hypocalciuric hypercalcaemia (FHH) Elevated (PMID: 26082470, 23222959) osteomalacia
CASR CASR-related conditions elevated hypercalcemia hypocalciuria, hyperplastic parathyroid gland, elevated parathyroid hormone
CDC73 hyperparathyroidism jaw tumor syndrome 80% by age 40 (PMID: 20301744) parathyroid cancer— up to 15% (PMID: 20301744, 22302605) ossifying jaw tumors, hamartomas, renal cysts, Wilms tumor, uterine fibroids
CDKN1B multiple endocrine neoplasia type 4 (MEN4) elevated (PMID: 23933118, 23140918) parathyroid adenomas pituitary adenomas, pancreatic NETs
GNA11 autosomal dominant hypocalcemia (ADH), familial hypocalciuric hypercalcemia (FHH) Elevated (PMID: 8194446, 23802536, 23802516, 24823460, 26729423)
MEN1 multiple endocrine neoplasia type 1 (MEN1) up to 100% (PMID: 19904212) parathyroid adenomas pituitary adenomas, pancreatic NETs, carcinoids, benign thyroid lesions, meningioma, lipoma, adrenocortical carcinoma—1%–13% lifetime risk (PMID: 22084155)
RET multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B) elevated parathyroid hyperplasia—20%–30% (PMID: 24899893) medullary thyroid cancer, pheochromocytomas, distinctive facies (MEN2B), intestinal ganglioneuromas

Elevated: There is evidence of association, but the penetrance and risk are not well characterized.

Most of the genes on this panel confer an increased risk of developing hyperparathyroidism in an autosomal dominant inheritance pattern. CASR has both autosomal dominant and autosomal recessive inheritance.

Invitae’s hyperparathyroidism panel may be considered for individuals with the following:

  • hyperparathyroidism with low urine calcium excretion
  • early onset hyperparathyroidism
  • a family history of hypercalcemia
  • ossifying fibroma(s) of the maxilla or mandible
  • parathyroid carcinoma

  1. Falchetti, A, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet. Med. 2009; 11(12):825-35. doi: 10.1097/GIM.0b013e3181be5c97. PMID: 19904212
  2. Marquard, J, Eng, C. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1257/ PMID: 20301434
  3. Wang, TT, et al. Two cases of multiple ossifying fibromas in the jaws. Diagn Pathol. 2014; 9:75. doi: 10.1186/1746-1596-9-75. PMID: 24678936
  4. Thakker, RV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol. Cell. Endocrinol. 2014; 386(1-2):2-15. doi: 10.1016/j.mce.2013.08.002. PMID: 23933118
  5. Pannett, AA, et al. Multiple endocrine neoplasia type 1 (MEN1) germline mutations in familial isolated primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2003; 58(5):639-46. doi: 10.1046/j.1365-2265.2003.01765.x. PMID: 12699448
  6. Vergés, B, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 2002; 87(2):457-65. doi: 10.1210/jcem.87.2.8145. PMID: 11836268
  7. Gorvin, CM, et al. A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2). J. Bone Miner. Res. 2016; 31(6):1200-6. PMID: 26729423
  8. Li, D, et al. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization. J. Clin. Endocrinol. Metab. 2014; 99(9):E1774-83. PMID: 24823460
  9. Mannstadt, M, et al. Germline mutations affecting Gα11 in hypoparathyroidism. N. Engl. J. Med. 2013; 368(26):2532-4. PMID: 23802536
  10. Schulz, KD. [Metastases in breast carcinoma]. Dtsch. Med. Wochenschr. 1994; 119(20):750. PMID: 8194446
  11. Hannan, FM, et al. Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects. Hum. Mol. Genet. 2015; 24(18):5079-92. PMID: 26082470
  12. Nesbit, MA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 2013; 45(1):93-7. PMID: 23222959
  13. Thakker, RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S272-4. PMID: 23565397
  14. Villablanca, A, et al. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur. J. Endocrinol. 2002; 147(3):313-22. PMID: 12213668
  15. Asgharian, B, et al. Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1. J. Clin. Endocrinol. Metab. 2004; 89(11):5328-36. doi: 10.1210/jc.2004-0218. PMID: 15531478
  16. Miedlich, S, et al. Familial isolated primary hyperparathyroidism--a multiple endocrine neoplasia type 1 variant?. Eur. J. Endocrinol. 2001; 145(2):155-60. PMID: 11454510
  17. Norton, JA, et al. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015; 24(4):795-832. PMID: 26363542
  18. Shibata, Y, et al. Early-onset, severe, and recurrent primary hyperparathyroidism associated with a novel CDC73 mutation. Endocr. J. 2015; 62(7):627-32. doi: 10.1507/endocrj.EJ15-0057. PMID: 25959515
  19. Kutcher, MR, et al. Hyperparathyroidism-jaw tumor syndrome. Head Neck. 2013; 35(6):E175-7. PMID: 22302605
  20. Pasquali, D, et al. Multiple endocrine neoplasia, the old and the new: a mini review. G Chir. 2012; 33(11-12):370-3. PMID: 23140918
  21. Guarnieri, V, et al. Diagnosis of parathyroid tumors in familial isolated hyperparathyroidism with HRPT2 mutation: implications for cancer surveillance. J. Clin. Endocrinol. Metab. 2006; 91(8):2827-32. PMID: 16720667
  22. Choi, KH, et al. Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C. Korean J Pediatr. 2015; 58(4):148-53. PMID: 25932037
  23. Vezzoli, G, et al. Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J. Nephrol. 2006; 19(4):525-8. PMID: 17048213
  24. Watanabe, S, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet. 2002; 360(9334):692-4. PMID: 12241879
  25. Frank-Raue, K, et al. Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism. Clin. Endocrinol. (Oxf). 2011; 75(1):50-5. PMID: 21521328
  26. Roizen, J, Levine, MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012; 75(9):425-34. PMID: 22989537
  27. Nagase, T, et al. A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor. J. Clin. Endocrinol. Metab. 2002; 87(6):2681-7. PMID: 12050233
  28. Gatta-Cherifi, B, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database. Eur. J. Endocrinol. 2012; 166(2):269-79. doi: 10.1530/EJE-11-0679. PMID: 22084155
  29. Egbuna, OI, Brown, EM. Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Clin Rheumatol. 2008; 22(1):129-48. PMID: 18328986
  30. Ellard, S, et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin. Endocrinol. (Oxf). 2005; 62(2):169-75. doi: 10.1111/j.1365-2265.2005.02190.x. PMID: 15670192
  31. Moline, J, Eng, C. Multiple endocrine neoplasia type 2: an overview. Genet. Med. 2011; 13(9):755-64. PMID: 21552134
  32. Nesbit, MA, et al. Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia. N. Engl. J. Med. 2013; 368(26):2476-2486. PMID: 23802516
  33. Hyde SM, et al. CDC73-Related Disorders. 2008 Dec 31. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK3789/ PMID: 20301744
  34. Brandi, ML, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J. Clin. Endocrinol. Metab. 2001; 86(12):5658-71. doi: 10.1210/jcem.86.12.8070. PMID: 11739416
  35. Carpten, JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 2002; 32(4):676-80. PMID: 12434154
  36. Wang, O, et al. Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PLoS ONE. 2012; 7(9):e45567. PMID: 23029104
  37. Bricaire, L, et al. Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2013; 98(2):E403-8. PMID: 23293331
  38. Parfitt, J, et al. Tumor suppressor gene mutation in a patient with a history of hyperparathyroidism-jaw tumor syndrome and healed generalized osteitis fibrosa cystica: a case report and genetic pathophysiology review. J. Oral Maxillofac. Surg. 2015; 73(1):194.e1-9. doi: 10.1016/j.joms.2014.09.008. PMID: 25511968
  39. Iacobone, M, et al. Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred. Langenbecks Arch Surg. 2009; 394(5):817-25. doi: 10.1007/s00423-009-0511-y. PMID: 19529956
  40. Thakker, RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J. Clin. Endocrinol. Metab. 2012; 97(9):2990-3011. doi: 10.1210/jc.2012-1230. PMID: 22723327
  41. Pannett, AA, Thakker, RV. Multiple endocrine neoplasia type 1. Endocr. Relat. Cancer. 1999; 6(4):449-73. PMID: 10730900
  42. Christensen, SE, et al. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes. 2011; 18(6):359-70. PMID: 21986511
  43. Warner, J, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J. Med. Genet. 2004; 41(3):155-60. PMID: 14985373
  44. Thim, SB, et al. Activating calcium-sensing receptor gene variants in children: a case study of infant hypocalcaemia and literature review. Acta Paediatr. 2014; 103(11):1117-25. PMID: 25039540
  45. Giusti, F, et al. Multiple Endocrine Neoplasia Type 1. 2005 Aug 31. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1538/ PMID: 20301710
  46. Bradley, KJ, et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 2005; 257(1):18-26. doi: 10.1111/j.1365-2796.2004.01421.x. PMID: 15606373

Most individuals with hereditary hyperparathyroidism are followed by an endocrinology specialist and medical management is based on a comprehensive assessment.

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
AP2S1 NM_004069.4
CASR NM_000388.3
CDC73 NM_024529.4
CDKN1B NM_004064.4
GNA11 NM_002067.4
MEN1 NM_130799.2
RET NM_020975.4