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CMMRD – genetic testing

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  • An individual with a clinical presentation that meets the testing threshold for constitutional mismatch repair deficiency (CMMRD)r*
  • An individual who has not had cancer but is at risk of inheriting biallelic pathogenic variants in a mismatch repair (MMR) gene because:
    1. both of their parents have a known germline pathogenic variant in an MMR gene^ OR
    2. a full sibling is known to have CMMRD^
  • Where testing of a person suspected to have CMMRD has not been possible, testing of an unaffected first degree relative may be indicated as monoallelic pathogenic variants in the MMR genes are associated with Lynch syndrome.
  • 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. 

Genetic testing is important for good clinical care of individuals who are suspected of having biallelic pathogenic variants in a MMR gene (i.e. suspected to have CMMRD).

See also MMR genetic testing (for monoallelic MMR pathogenic variants)

*Constitutional mismatch repair deficiency is caused by biallelic pathogenic variants in a MMR gene

The results of the following investigations may significantly influence the likelihood of detecting heritable biallelic pathogenic variants in the MMR genes:

  • Immunohistochemistry (IHC) for the MMR proteins MLH1, MSH2, MSH6 and PMS2 can be performed on tumour and/or normal tissue (e.g. skin biopsy or normal colonic mucosa).
    • IHC loss of 1 (or 2) of the MMR proteins in both tumour and normal tissue correlates highly with CMMRD.
  • Microsatellite instability (MSI) should not be used as the initial screening test for CMMRD. MSI is neither sensitive nor specific for CMMRD.r
  • Tumours which are hypermutant may be associated with underlying CMMRD and testing should be considered.

The probability of biallelic heritable pathogenic variants in the MMR genes remains uncertain due to the small study numbers.

Factors  Probability of detecting biallelic heritable pathogenic variants
Score of >3 points on scoring system Highr
Tumour features e.g. mismatch repair deficiency in both tumour tissue and normal tissue 100%r
Sibling with biallelic MMR pathogenic variants 25% chance of biallelic pathogenic variants (CMMRD)
Factors  Probability of detecting a monoallelic heritable pathogenic variant (Lynch syndrome)
Parent of child with CMMRD 100%
Sibling of child with CMMRD 50%

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

A range of testing methodologies is needed to identify pathogenic changes in the MMR genes including:

  • sequencing
  • copy number analysis (e.g. including EPCAM gene)
  • methylation analysis
  • analysis for structural rearrangements (e.g. MSH2 inversion)
  • testing of the PMS2 gene, which can be difficult due to the presence of pseudogenes. Consideration should be given to long range PCR of the whole gene if a pathogenic variant is not found with conventional testing.

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 these genes 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.

If these genes are tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology should be considered.

If genetic testing in DNA from peripheral blood does not identify a pathogenic variant, testing of other tumour and tissue samples may be indicated to assess for mosaicism.

The interpretation of results for suspected CMMRD may be complex. Discussion with a clinical genetics service and/or genetic pathology laboratory is recommended. Information about result interpretation has been published.r See CMMRD diagnostic criteria

Result  Reference databases  Considerations and advice
Pathogenic variant search
Biallelic pathogenic variant

ClinVar

UMD

LOVD

InSIGHT

 CMMRD - risk management
Monoallelic pathogenic variant

MMR genes (Lynch syndrome) – risk management

If the clinical presentation is strongly suggestive of CMMRD, may have a cryptic pathogenic variant
Variant of uncertain significance Identify other genes for which a pathogenic variant search could be considered e.g. NF1, Fanconi anaemia, Bloom syndrome
No reportable variant Identify other genes for which a mutation search could be considered e.g. NF1, Fanconi anaemia, Bloom syndrome
Predictive testing
Biallelic family pathogenic variants identified   CMMRD - risk management
Monoallelic family pathogenic variants identified   MMR genes (Lynch syndrome) – risk management
Family pathogenic variants not found   Screening based on revised estimate

If biallelic or monoallelic pathogenic variants are identified refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing. 

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).

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

If no pathogenic variants are identified consider referral to a clinical genetics service or familial cancer centre for consideration of other genetic diagnoses.

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 4

Date Summary of changes
23/02/2023

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

  • Target population: 
    • Added "Where a 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."
  • 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.4.

Version 3

Date Summary of changes
28/10/2021

Protocol reviewed at July 2021 paediatric reference committee meeting. Discussion continued via email and MS Teams. Approved for publication with the following changes made: 

  • Target population:
    • Bullet 1: changed to 'An individual with a clinical presentation that meets the testing threshold for constitutional mismatch repair deficiency (CMMRD)'
  • Indications before genetic testing:
    • Bullet 3: added 'Tumours which are hypermutant may be associated with underlying CMMRD and testing should be considered.'
  • Probability of a heritable pathogenic variant
    • Row 2: deleted 'Certain tumours: carcinoma from Lynch syndrome spectrum at age <25 years, multiple bowel adenomas at age <25 years after exclusion of APC and MUTYH pathogenic variants'  (row 2 of table) as this is covered in the 'Score of ≥3 points on scoring system' (row 1 of table)
  • Testing methods: link to 'European Directory of DNA Diagnostic Laboratories' removed as website no longer available
  • Result interpretation:
    • Added above the table 'The interpretation of results for suspected CMMRD may be complex. Discussion with a clinical genetics service and/or genetic pathology laboratory is recommended. Information about result interpretation has been published. See CMMRD diagnostic criteria' 
    • Template formatting changes applied to table
    • Added below the table 'If a variant of uncertain significance is identified refer to a clinical genetics service or familial cancer centre for review and guidance.'

Version increased to V.3. Review in 2 years.

Version 2

Date Summary of changes
03/02/2021

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

  • Related pages: added links to "Guide for health professionals ordering genetic testing" and "Cancer predisposition genes: population carrier frequency". Removed link to "Pre-test counselling"
  • Target population: wording changes
  • Circumstances in which testing is not indicated: template wording added
  • Testing methods: template wording updated
  • Result interpretation:
    • Table format updated
    • Reference databases added
    • Added "If no pathogenic variants are identified consider referral to a clinical genetics service or familial cancer centre for consideration of other genetic diagnoses."
    • Template sentence added including link to "Guide for health professionals ordering genetic testing"
  • Counselling: section deleted
  • Website resources: section deleted
  • Version number increased to V.2.

Version 1

Date Summary of changes
17/12/2019 New protocol developed and discussed by the cancer genetics paediatric reference committee at the July 2019 reference committee meeting. Protocol approved for publication as V.1. Review in 1 year.

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/3728

10 Sep 2024