CMMRD genetic testing

• 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 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.

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.

A variant-specific test (rather than a panel test) 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.

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:

• RCPA catalogue of genetic tests and laboratories
• GeneReviews^®
• Genetic Testing Registry
• NHS National Genomic Test Directory

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 does not identify a pathogenic variant, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour 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

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 refer 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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