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CMMRD genetic testing

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  • In an individual with a cancer diagnosis who meets the following:
    • ​​​personal history of Lynch syndrome-related cancer* <25 years
    • multiple bowel adenomas <25 years, after exclusion of APC and MUTYH pathogenic variants
    • clinical presentation meets testing threshold
  • Where a known pathogenic variant is identified in a relative
  • Where testing of an affected person has not been possible, testing of an unaffected first degree relative may be indicated as monoallelic pathogenic variants in the mismatch repair (MMR) genes are associated with Lynch syndrome.

Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.

* Includes colorectal, endometrial, ovarian, small bowel, ureter, renal pelvis, biliary tract, stomach, bladder

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

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

Factors  Probability of detecting a biallelic heritable pathogenic variant
Score of >3 points on scoring system Highr

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
 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 when only a variant of uncertain significance or a benign/likely benign variant has been identified in a family.

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

  • sequencing
  • copy number analysis (e.g. MLPA, 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:

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 is uninformative, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

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

ClinGen

InSiGHT

 CMMRD - risk management
Monoallelic pathogenic variant

ClinGen

InSiGHT

MMR genes (Lynch syndrome) – risk management

If the clinical presentation is strongly suggestive of CMMRD, may have a cryptic pathogenic variant
Inconclusive

ClinGen

InSiGHT

 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).

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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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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First approved:
Review due:

The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3728

28 Mar 2020