• Test code: 01707
  • 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

Invitae Hereditary Diffuse Gastric Cancer Syndrome Test

Test description

This test analyzes the CDH1 gene, which is associated with hereditary diffuse gastric cancer syndrome (HDGC). This condition results in an increased risk of both gastric and lobular breast cancer.

Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Order test

Primary panel (1 gene)

Alternative tests to consider

HGDC can also be ordered as part of a larger panel to test for different types of hereditary cancer, including breast and colon cancers. Depending on the individual’s clinical and family history, one of these larger panels may be appropriate. Any of these larger panels can be ordered for no additional charge.

  • hereditary diffuse gastric cancer (HGDC)

Hereditary diffuse gastric cancer (HDGC) is an adult-onset hereditary cancer syndrome that increases an individual’s risk of developing diffuse gastric cancer. Diffuse gastric cancer is a type of adenocarcinoma that infiltrates and thickens the stomach wall without forming a distinct tumor mass. Signet ring cells are often observed throughout the stomach wall. Symptoms typically present in advanced disease and can include stomach pain, nausea, vomiting, difficulty swallowing, decreased appetite, and weight loss.

Individuals with HDGC have up to an 83% risk of developing diffuse gastric cancer. The average age of onset of gastric cancer is 38 years, with a range of 14 years to 69 years. Women with this inherited predisposition also have an approximately 52% risk of developing lobular carcinoma of the breast. There is also evidence to suggest that orofacial clefts may be a feature of HDGC.

Individuals with a pathogenic CDH1 variant have an increased risk of malignancy compared to the average person, but not everyone with a pathogenic variant will actually develop cancer. Further, HGDC is variable, meaning individuals with the same condition may present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant.

The lifetime risk for developing gastric cancer in those with a pathogenic variant in CDH1 is 67-80% for men and 56-83% for women. Women have a 39%-52% risk for lobular breast cancer.

Pathogenic variants are identified in 30%-50% of affected individuals. Deletion/duplication analysis identifies an additional 4% of cases.

HDGC is inherited in an autosomal dominant pattern. Most cases are inherited from a parent. Spontaneous de novo mutations are uncommon.

Gastric cancer is the fourth-commonest cancer worldwide, but less than 1% of these cases are due to HDGC.

Testing for CDH1 may be considered for individuals with the following:

  • diffuse gastric cancer before the age of 40 years
  • bilateral or familial lobular breast cancer before the age of 50 years
  • diffuse gastric cancer and cleft lip/palate
  • precursor lesions for signet ring cell carcinoma

Clinical diagnostic criteria for HDGC have been developed by the International Gastric Cancer Linkage Consortium in 2010

  1. van, der, Post, RS, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J. Med. Genet. 2015; 52(6):361-74. doi: 10.1136/jmedgenet-2015-103094. PMID: 25979631
  2. Pharoah, PD, et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001; 121(6):1348-53. doi: 10.1053/gast.2001.29611. PMID: 11729114
  3. Kaurah, P, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007; 297(21):2360-72. doi: 10.1001/jama.297.21.2360. PMID: 17545690
  4. Benusiglio, PR, et al. Cleft lip, cleft palate, hereditary diffuse gastric cancer and germline mutations in CDH1. Int. J. Cancer. 2013; 132(10):2470. doi: 10.1002/ijc.27923. PMID: 23124477
  5. Vogelaar, IP, et al. Identification of germline mutations in the cancer predisposing gene CDH1 in patients with orofacial clefts. Hum. Mol. Genet. 2013; 22(5):919-26. doi: 10.1093/hmg/dds497. PMID: 23197654
  6. Kluijt, I, et al. CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int. J. Cancer. 2012; 131(2):367-76. doi: 10.1002/ijc.26398. PMID: 22020549
  7. Kaurah, P, Huntsman, DG. Hereditary Diffuse Gastric Cancer. 2002 Nov 04. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1139/ PMID: 20301318
  8. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  9. Fitzgerald, RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J. Med. Genet. 2010; 47(7):436-44. doi: 10.1136/jmg.2009.074237. PMID: 20591882
  10. Frebourg, T, et al. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer. J. Med. Genet. 2006; 43(2):138-42. doi: 10.1136/jmg.2005.031385. PMID: 15831593
  11. National Comprehensive Cancer Network®, Clinical practice guidelines in oncology. Genetic/Familial High Risk Assessment: Breast and Ovarian. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp Accessed January 2018.
  12. American Society of Clinical Oncology, Cancer.Net: Hereditary diffuse gastric cancer. http://www.cancer.net/cancer-types/hereditary-diffuse-gastric-cancer Accessed January 2018.
  13. National Library of Medicine, Genetics Home Reference: CDH1. http://ghr.nlm.nih.gov/gene/CDH1 Accessed June 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, +/- 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
CDH1 NM_004360.3