Hereditary Diffuse Gastric Cancer (HDGC)

Hereditary diffuse gastric cancer (HDGC) is a highly penetrant, yet rare, autosomal dominant condition that predisposes to diffuse gastric cancer and lobular breast cancer.  It accounts for <1% of all gastric cancers and is caused by mutations in the CDH1 gene.
Quick Reference
Test Code: 4722 Test Name: CDH1 specific site analysis TAT: 7-14 days Genes: 1
Test Code: 4726 Test Name: CDH1 seq and del/dup TAT: 14-21 days Genes: 1

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We offer family variant testing at no additional cost

We offer family variant testing for all blood relatives of patients who undergo full single gene sequencing, multigene panel testing or exome sequencing at Ambry Genetics and are found to have a pathogenic or likely pathogenic variant. Testing must be completed within 90 days of the original report date. Whenever possible, more closely related relatives should be tested before more distant relatives. If you or a family member are interested in learning more about our family testing program or when family testing may be clinically indicated, please contact us or your provider for additional information. Note that Ambry can only provide such family testing services to patients receiving medical care in the U.S or US territories.

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Why Is This Important?

  1. Option to modify frequency and initial age of mammogram/breast MRI, colonoscopy, or other screening as appropriate
  2. Consideration of prophylactic surgery, such as gastrectomy, or other risk-reducing measures, as appropriate 
  3. Identify at-risk family members 

When To Consider Testing

  • An indvidual who meets the diagnostic criteria for HDGC (see details below)
  • Bilateral lobular breast cancer 
  • Family history of 2 or more cases of LBC diagnosed before 50y
  • A personal or family history of cleft lip/palate in a patient with diffuse gastric cancer 
  • In situ signet ring cells and/or pagetoid spread of signet ring cells on pathology

According to the International Gastric Cancer Linkage Consortium (IGCLC), an individual has a clinical diagnosis of HDGC if any of the following criteria are met:1

  • >2 cases of gastric cancer in first- or second-degree relatives, with 1 or more confirmed cases of diffuse gastric cancer (DGC) diagnosed before age 50
  • >3 cases of DGC in first- or second-degree relatives, diagnosed at any age 
  • An individual with DGC, diagnosed before 40y
  • A personal or family history of DGC LBC, with at least one case diagnosed before 50y

Mutation Detection Rate

Ambry’s CDH1 testing is capable of detecting greater than 99.9% of described mutations in the gene, when present (analytic sensitivity).

Test Description

CDH1 coding exons 1-16 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-16. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using a standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by incorporating the gDNA onto a microfluidics chip, along with primer pairs followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing, or with insufficient read depth coverage for reliable heterozygous variant detection. Potentially homozygous variants, variants in regions complicated by pseudogene interference, and variant calls not satisfying depth of coverage and variant allele frequency quality thresholds are verified by Sanger sequencing. Gross deletion/duplication analysis of CDH1 using multiplex ligation-dependent probe amplification (MLPA) is also performed.

1. Fitzgerald RC, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010; 47:436-444.

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