Germline MMR gene (MLH1, MSH2, MSH6, PMS2 and/or EPCAM deletions) testing should be considered:
- Where assessment of mismatch repair is possible in the tumour
- An individual diagnosed with a mismatch repair deficient (MMR deficient) tumour^ at any age^^ (see flow chart).
- An individual with a MMR proficient tumour which is part of the Lynch syndrome tumour spectrum# where there is a family history of a Lynch spectrum tumour OR a family history which meets Amsterdam I or II criteria (false negative MMR tumour status could be due to a missense or splice-site pathogenic variantr or other technical/interpretation issues).
- Where tumour testing has not been possible
- An individual diagnosed with a tumour which is part of the Lynch syndrome tumour spectrum# (usually colorectal or endometrial) diagnosed age <50 years where no tumour testing is possible.
- An individual diagnosed with a Lynch syndrome tumour spectrum# cancer where tumour testing is not possible and one of the following high-risk factors e.g. family history that meets Amsterdam I or II criteria, second Lynch syndrome tumour unable to be tested, relative with MMR-deficient cancer.
- Where a known germline pathogenic variant is 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.
Genetic testing is important for good clinical care of individuals who are suspected of having a heritable pathogenic variant in these genes.
^tumour mismatch repair deficiency defined as 1) high levels of microsatellite instability (MSI-H) by polymerase chain reaction (PCR) or next generation sequencing (NGS) or 2) by abnormal loss of MMR protein expression on immunohistochemistry (IHC).
^^exclusion of tumours with MLH1 gene promoter hypermethylation or colorectal cancers with BRAF c.1799T>A p. Val600Glu (BRAF p.V600E) somatic mutation increases the likelihood of identifying a germline pathogenic variant in a person with a MLH1/PMS2 deficient tumour.
#Lynch syndrome tumour spectrum includes colorectal, endometrial, gastric, ovarian, pancreatic, urothelial, brain (usually glioblastoma), biliary tract, and small intestine, as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas as seen in Muir-Torre syndrome.