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CDH1 – genetic testing

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  • An individual with diffuse gastric cancer (DGC) before age 50 years
  • An individual with DGC at any age and one or more of:
    • Maori ethnicity
    • personal or family history of cleft lip or cleft palate
    • one or more first/second degree relative/s with gastric cancer at any age, where there is at least one confirmed DGC
    • one or more first/second degree relative/s with lobular breast cancer, with one case diagnosed before age 70 years
  • An individual with DGC and lobular breast cancer, both diagnosed before age 70 years
  • An individual with bilateral lobular breast cancer before age 50 years
  • An individual with gastric in situ signet ring cells or pagetoid spread of signet ring cells before age 50 years
  • An individual with lobular breast cancer who has one or more first/second degree relative/s with DGC, with one case diagnosed before age 70 years
  • An individual with lobular breast cancer before age 50 years who has one or more first/second degree relative/s with lobular breast cancer, diagnosed before age 50 years.

Note: When a criterion involves two or more cancers, at least one cancer should have confirmed histology.

These genetic testing criteria are based on the 2020 International Gastric Cancer Linkage Consortium Criteria for testingr with the exception of bilateral lobular breast cancer which remains based on the 2015 criteria.r

Where possible, test an affected person. If there are no living affected relatives, consider tissue testing (tumour tissue and/or healthy tissue) from an affected deceased relative. If these options are not available, consider testing unaffected first degree relatives.

Note
  • where a known germline pathogenic variant has been identified in a relative*
  • where a specific pathogenic variant has been identified on somatic tumour testing *

*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective. 

The decision to offer a genetic test should be based on the pre-test probability of identifying a heritable pathogenic variant, the performance of the test (e.g. false negative rate).

The results of the following investigations (in patient and/or relatives) may significantly influence the likelihood of detecting a germline pathogenic variant in the CDH1 gene:

  • molecular and histopathological confirmation of diffuse type gastric carcinoma, or poorly cohesive carcinomas, including signet ring cell carcinoma, in at least one individual
  • molecular and histopathological confirmation of lobular breast carcinoma (including e-Cadherin staining)
  • immunohistochemistry for mismatch repair proteins on gastric cancer tissue.

Germline CDH1 pathogenic variants are a significant contributor to the high frequency of DGC in New Zealand Maori.r

A 2012 meta-analysis suggested that the frequency of CDH1 germline pathogenic variants is higher in geographic regions with low gastric cancer risks, compared to regions with moderate-to-high risks.r

The rate of de novo heritable pathogenic variants in the CDH1 gene is unknown, but low.

Factors  Probability of detecting a heritable pathogenic variant
Family fulfils 2020 International Gastric Cancer Linkage Consortium criteria for testingr 7-19%r
Family fulfils 2020 International Gastric Cancer Linkage Consortium criteria for testingr 14-19%r
New Zealand Maori with DGC

34% overallr

67% if diagnosed age <45 yearsr
Affected individual age <40 years, and is an isolated case DGC 10%r
Bilateral invasive lobular carcinoma age <70 years (not mixed pathology) 7%r
Patient has a first or second degree relative with documented pathogenic variant Up to 50%
  • Probands with histologically confirmed intestinal-type gastric cancer in a family where there are no confirmed cases of diffuse type gastric adenocarcinoma and/or bilateral lobular breast cancer  
  • Mismatch repair deficient gastric cancer

There is no evidence for CDH1 testing in the context of familial breast cancer where there is no family history of DGC and/or lobular breast cancer.

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

A range of testing methodologies are needed to identify pathogenic changes in the CDH1 gene including:

  • sequencing
  • copy number analysis (e.g. MLPA).

Information about DNA tests and testing laboratories is available from:

A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour.

If a decision is made to test this gene as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

UMD

LOVD

InSiGHT

CDH1 - risk management
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered
No reportable variant  

Identify other genes for which a pathogenic variant search could be considered 
Predictive testing
Family pathogenic variant identified  

CDH1 - risk management
Family pathogenic variant not found  

Screening based on revised risk estimate

If a pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

If a mosaic pathogenic variant is identified, refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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Version 9

Date Summary of changes
20/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template:

  • Target population: 
    • Added: "Where a known germline pathogenic variant has been identified..."
    • Added "where a specific pathogenic variant has been identified on somatic tumour testing *"
    • Added "*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective."
    • "a patient's choice" removed from "The decision to offer a genetic test should be based on the pre­test probability of identifying a heritable pathogenic variant and the performance of the test (e.g. false negative rate)."
  • Circumstances in which testing is not indicated:
    •  Removed "A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where: 
      • a known pathogenic variant has been identified in a relative
      • a specific pathogenic variant has been identified on somatic tumour testing."
  • Testing methods:
    • Added "A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour."
  • Result interpretation:
    • HGMD and DMuDB removed from table.
    • Template sentence added.

Version increased to V.9. 

Version 8

Date Summary of changes
28/04/2021

Protocol reviewed at October 2020 reference committee meeting. Discussions continued via email and MS Teams. New 2020 eviQ template changes applied. Approved for publication with the following changes made:

  • Target population: completely rewritten
  • Investigations before genetic testing:
    • sentence 1: inserted '(in patient and/or relatives)'
    • bullet 1: deleted '(WHO classification)'
    • new bullets 2 and 3 inserted
  • Probability of a heritable pathogenic variant:
    • Inserted: 'Germline CDH1 pathogenic variants are a significant contributor to the high frequency of diffuse gastric cancer in New Zealand Maori'
    • 'Of the heritable pathogenic variants identified in the CDH1 gene, there has been only a single a case report of a de novo pathogenic variant.' changed to read 'The rate of de novo heritable pathogenic variants in the CDH1 gene is unknown, but rare.'
    • Table row 1: '2010' changed to '2020'
    • Table row 3: 'Affected individual <40, and is an isolated case DGC' changed to 'New Zealand Maori with diffuse gastric cancer'
    • Table row 4: 'Affected individual <50 of NZ Maori ancestry' changed to 'Affected individual age <40 years, and is an isolated case DGC'
    • Table row 5: 'Bilateral LCIS or LBC <50 yrs' changed to 'Bilateral invasive lobular carcinoma age <70 years'
    • Table column 2: all figures replaced
  • Circumstances in which testing is not indicated:
    • Bullet 1 updated to read: 'Probands with histologically confirmed intestinal-type gastric cancer in a family where there are no confirmed cases of diffuse type gastric adenocarcinoma and/or bilateral lobular breast cancer'
    • Bullets 2 and 3 deleted
    • New bullet 2 inserted: 'Mismatch repair deficient gastric cancer'
    • Template changes inserted: 'A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where:
      • a known pathogenic variant has been identified in a relative
      • a specific pathogenic variant has been identified on somatic tumour testing.'
  • Testing methods: links updated
  • Result interpretation:
    • table: template changes applied and reference databases added 
    • 3 new template sentences inserted after table
  • Counselling: deleted per template changes
  • Website resources: deleted 'The European Molecular Genetics Quality Network'

Version number increased to V.8. Review in 2 years.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 7

Date Summary of changes
18/11/2019
  • "Mutation" changed to "pathogenic variant" and "unclassified variant" changed to "variant of uncertain significance" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs
  • Definition of "pathogenic variant" added as a pop-up

Version number increased to V.7.

Version 6

Date Summary of changes.
05/09/2011 Approved at September cancer genetics reference committee meeting.
04/09/2013

Discussed at August 2012 reference committee meeting and discussion continued via email and the following changes made: 

  • Reformatted according to new template.
  • Investigations which should be considered before germline testing - updated.
  • Factors which influence the pre-test probablity of a germline mutation - updated.
  • De novo mutations in the CDH1 gene have not been reported deleted
    Added Of the heritable mutations identified in the CDH1 gene, there has been only a single a case report of a de novo mutation.
  • Circumstances in which testing is not indicated - updated.
  • Review second yearly.
26/03/2104

Following discussion at March 5 2014 reference committee meeting the following change has been made:

  • Diagnostic testing - Link to Human Genetics Society of Australasia removed.
30/09/2015 Sentence added to Genetic Testing protocol template: "If a decision is made to test this gene(s) as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility".
26/02/2016

Reviewed at October 2015 reference committee meeting and discussions continued via email. The following changes have been made:

  • Target population - wording and IGCLC criteria document updated.
  • Investigations which should be considered before germline genetic testing - updated.
  • Factors which influence the pre-test probability of a heritable mutation - updated.
  • Diagnostic testing - updated according to new template.
  • References - updated. 
  • For 2 yearly review.
31/05/2017 Transferred to new eviQ website. Version number changed to V.4.
2/05/2018

Protocol reviewed and presented at the November 2017 eviQ Cancer Genetics  reference committee meeting. Discussion continued over email and document approved for publication with the following changes: 

  • Reference list updated, Inclusion of the NZ Maori population as a factor in the probability of a heritable mutation, version change to V.5.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the CDH1 gene' to 'CDH1 genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1080

10 Sep 2024