DiagMMR validation study confirms accuracy of test for Lynch syndrome diagnosis

DiagMMR validation study confirms accuracy of test for Lynch syndrome diagnosis

The LS CancerDiag research team, led by CSO Minttu Kansikas, Ph.D., recently published a peer-reviewed article in Cancer Research Communications (March 2023). The article provides results for the clinical validation of the DiagMMR test based on the elaborate work the team has conducted during the past years. We are proud to present the results that indicate the high accuracy of the functional DiagMMR test in identifying individuals with inherited deficiency of the mismatch repair function. The function plays a vital role in cancer development. Furthermore, the test was shown to have an exceptional specificity (100%) and high sensitivity and accuracy, overcoming the complexity of other existing testing methods, and improving the ability to recognize individuals with Lynch syndrome.

We have gathered here the highlights and main points of the DiagMMR validation article:

  • Lynch syndrome (LS) is the most common hereditary cancer syndrome. Early diagnosis improves prognosis and reduces health care costs, through cancer surveillance methods. The problem is finding and diagnosing the cancer-predisposing genetic condition.
  • An inherited mismatch repair (MMR) deficiency is a hallmark of LS. We have developed and validated a functional MMR test, DiagMMR, that detects inherited MMR deficiency directly from healthy tissue without the need of tumor and variant information. 
  • LS diagnostics has lacked a predictive stand-alone method, which could change the course toward proactive recognition and surveillance of LS carriers before cancer appearance; a method for accurate LS identification, while also relieving non-LS families and non-carriers in LS families from lifelong clinical follow-up programs.
  • The purpose of the study was to clinically validate the DiagMMR test and determine its specificity and sensitivity for detecting LS caused by the MSH2 and MSH6 The study included people who had been confidently identified as LS cases.
DiagMMR Validation Workflow
  • Sample collection (119 samples altogether) was organized at the Helsinki University Central Hospital (HUCH) and Jyväskylä Central Hospital, Finland. For the clinical validation, skin samples were collected from LS pathogenic variant carriers during their colonoscopy control visits, from controls, and from LS family members who had been called for genetic counseling as risk members but did not know their carrier status yet.
  • DiagMMR test results were interpreted as normal (proficient) MMR or reduced (deficient) MMR based on the MMR capability of the sample in relation to cut-off, which distinguishes MMR-proficient from MMR-deficient function. The DiagMMR method has been previously optimized with 259 skin samples to detect MMR deficiency caused by an inherited pathogenic variant in the MSH2 or MSH6
  • Of the 119 samples, 93 demonstrated inherited functional MMR proficiency (no-LS) and 24 MMR deficiency (LS) by DiagMMR, while two samples were repeatedly within 5% of the cut-off, inside the “gray area”. Comparing the DiagMMR test interpretations obtained for 98% (117/119) of the tested samples with the LS carrier statuses as per the reference standard, 90 control samples (90/90) were shown to be MMR proficient, demonstrating no FP and hence yielding an assay specificity of 100%. Similarly, for carriers of MSH2 or MSH6 variants, 24 of 27 samples were shown to be MMR deficient, yielding an assay sensitivity of 9%. The test accuracy demonstrates that 97.4% (114/117) of the time, the test will reveal a result comparable with the reference standard.
DiagMMR Validation Results
  • The ability to detect LS carriers of pathogenic MSH2 and MSH6 variants without tumor data presents a novel approach to identifying LS. To our knowledge, DiagMMR is currently the only validated and CE-marked functional test for LS (IVDD 98/79/EC). Using clinical diagnoses confirmed by sequencing as a reference standard for identifying MSH2 and MSH6 variant carriers, we show that DiagMMR has exceptionally high specificity (100%, no FP), sensitivity (89%), and accuracy (97%).
  • After the clinical validation study, the DiagMMR method was used to test seven LS-suspected individuals for whom conventional diagnostic methods had not given a definitive diagnosis. The clinical benefit of the DiagMMR test was further examined through this pilot study, where DiagMMR assisted in the diagnosis and clinical management of the tested patients by directing all MMR-deficient patients to regular clinical surveillance.
  • The DiagMMR test is shown to be a novel, minimally invasive method for detecting LS causing deficient MMR function from constitutional tissue. With high specificity and sensitivity, it offers an excellent LS cancer prediction and prevention strategy.


Kansikas, M., Vähätalo, L., Kantelinen, J., Kasela, M., Putula, J., Døhlen, A., … & Nyström, M. (2023). Tumor-independent detection of inherited mismatch repair deficiency for the diagnosis of Lynch syndrome with high specificity and sensitivity. Cancer research communications, 3(3), 361–370. https://doi.org/10.1158/2767-9764.CRC-22-0384.



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