• Test code: 01303
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

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)


  • 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

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  2. 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
  3. 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
  4. 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
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  11. 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
  12. Nesbit, MA, et al. Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3. Nat. Genet. 2013; 45(1):93-7. PMID: 23222959
  13. 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
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  15. Mannstadt, M, et al. Germline mutations affecting Gα11 in hypoparathyroidism. N. Engl. J. Med. 2013; 368(26):2532-4. PMID: 23802536
  16. 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
  17. 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
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  23. 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
  24. Carpten, JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 2002; 32(4):676-80. PMID: 12434154
  25. Moline, J, Eng, C. Multiple endocrine neoplasia type 2: an overview. Genet. Med. 2011; 13(9):755-64. PMID: 21552134
  26. 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
  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. Roizen, J, Levine, MA. Primary hyperparathyroidism in children and adolescents. J Chin Med Assoc. 2012; 75(9):425-34. PMID: 22989537
  29. 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
  30. Watanabe, S, et al. Association between activating mutations of calcium-sensing receptor and Bartter's syndrome. Lancet. 2002; 360(9334):692-4. PMID: 12241879
  31. Vezzoli, G, et al. Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome. J. Nephrol. 2006; 19(4):525-8. PMID: 17048213
  32. 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
  33. 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
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  35. Kutcher, MR, et al. Hyperparathyroidism-jaw tumor syndrome. Head Neck. 2013; 35(6):E175-7. PMID: 22302605
  36. Thakker, RV. Multiple endocrine neoplasia type 1. Indian J Endocrinol Metab. 2012; 16(Suppl 2):S272-4. PMID: 23565397
  37. Norton, JA, et al. Multiple Endocrine Neoplasia: Genetics and Clinical Management. Surg. Oncol. Clin. N. Am. 2015; 24(4):795-832. PMID: 26363542
  38. 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
  39. Villablanca, A, et al. Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism. Eur. J. Endocrinol. 2002; 147(3):313-22. PMID: 12213668
  40. 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
  41. 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
  42. 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
  43. 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
  44. 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
  45. 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
  46. 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

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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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

MEN1: Sequencing analysis for exons 2 includes only cds +/- 10 bp.