Systems approach to enhance Lynch syndrome diagnosis through tumour testing

J Med Genet. 2023 Jun;60(6):533-539. doi: 10.1136/jmg-2022-108770. Epub 2022 Sep 17.


Background: Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated.

Methods: This is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming.

Results: A total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention.

Conclusion: Implementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

Keywords: diagnosis; gastroenterology; health services research.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cohort Studies
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis* / pathology
  • DNA Mismatch Repair / genetics
  • Genetic Testing
  • Humans
  • MutL Protein Homolog 1 / genetics
  • Systems Analysis


  • MutL Protein Homolog 1