• Open Access

The educational role of external quality assessment in genetic testing: a 7-year experience of the European Molecular Genetics Quality Network (EMQN) in Lynch syndrome


  • Communicated by Finlay A. Macrae

Heterogeneous attitudes in genetic testing practice exist among countries in terms of access, acceptance, use, and rules. The European Molecular Genetics Quality Network (EMQN) is trying to harmonize genetic testing services across Europe by developing External Quality Assessment (EQA) schemes for different inherited disorders. One that EMQN focussed on early is Lynch syndrome (HNPCC) associated with inherited mutations in mismatch repair (MMR) genes. In addition to early-onset colorectal cancer, such mutations confer an increased risk of gynaecological, urinary tract, and gastrointestinal adenocarcinomas. Genetic testing results guide screening programs for patients and families as specific clinical guidelines have been proven to reduce morbidity and mortality [Grover and Syngal, 2010]. Unclear or misinformed laboratory reports have major clinical implications because the presence or absence of a pathogenic MMR mutation is often instrumental to decisions made about patient management. Since the first pilot scheme on the MMR genes organized in 2003, annual EQAs have enabled the identification of the most frequent difficulties encountered by the participating labs, addressing disease/gene-specific points to improve the standard of testing strategies (Table 1). Globally, the performance of laboratories in this scheme increased each year as well as the number of participants and a high technical standard of genotyping has been reached with the decreasing use of home-made reagents and manual procedures. This result is very encouraging for labs that aim to become referent with long-term agreements.

Table 1. Yearly EQA Schemes on the MMR Genes
Year2003 (pilot)200420052006200720082009
  • a

    aTargeted genes, exons, and type of alterations (point mutation or genomic rearrangement) to be searched were specified in the questions.

  • b

    bNumber of labs providing reports for all questions.

  • c

    cNumber of incorrect genotypes reported for the whole scheme.

  • d

    dInterpretation was not scored in case of genotyping error.

  • e

    eMean score ranges from 0.00 to 2.00 and corresponds to the mean of the individual interpretation scores obtained for each of the three cases; max score represents the number of labs (and percentage) who reached the best mean score, that is, 2.00.

Questions (3 per year)1 predictive+positive control, 2 diagnostic tests1 predictive+positive control, 2 diagnostic tests3 diagnostic tests3 diagnostic tests3 diagnostic tests3 diagnostic tests1 predictive+1 diagnostic confirmation, 2 diagnostic tests
Expected resultsa1 mutation carrier, 2 truncating mutations1 mutation carrier, 1 polymorphic missense, 1 deleterious missense1 splicing, 1 noncausative missense, 1 truncating mutation1 Start codon mutation, 1 truncating mutation, 1 polymorphism (Bat26)1 truncating mutation+1 noncausative missense, 1 deleterious missense, 1 truncating2 splicing mutations, 1 large deletion1 mutation carrier+1 confirmation, 1 noncausative missense, 1 large deletion
 Full reportb22 (71%)28 (67%)45 (92%)46 (90%)59 (92%)70 (86%)96 (89%)
 Genotyping errorsc04611231
 Correct interpretationd31/66 (47%)56/80 (70%)49/129 (38%)81/127 (64%)115/175 (66%)163/207 (79%)157/287 (55%)
 Mean scoree1.641.811.751.881.811.891.73
Max scoree0 (0%)10 (36%)1 (2%)10 (22%)20 (34%)34 (49%)24 (25%)

The feedback to the labs integrated the genotyping assessment and key points to improve the quality of the reports themselves. For example, in 2009, two separate reports were requested in one of the mock clinical questions—one for the index case (confirmation of the screening analysis) and one for a predictive test: 11 labs did not reanalyze the index case and 16 labs mixed the information from both cases in a single report, that is, 25% of the participants failed to write a reliable report for case 1. Best practice guidelines on reporting are available, which give clear guidance on the appropriate reporting procedures (http://www.sgmg.ch/view_page_professional.php?view=page&page_id=19). Specific to Lynch syndrome, the conclusion should have restated the genetic status in the clinical context with discussion on the patient's main risks (Lynch-related cancers, dominant inheritance) or the suitable prospective analyses. Before concluding the report, the reader should be convinced of the biological consequences of the genotype [Tavtigian et al., 2008]. In the 2008 scheme, 80% of participants provided consistent information because no case referred to missense variants. In contrast, the 2009 scheme (the same case was met in 2005) included such a situation and only 25% of them reached the maximum score [Adzhubei et al., 2010; Needham et al., 2006]. When analyzing separately the 78 labs having participated to both 2008 and 2009 schemes and the 34 participants newly registered in 2009, scores were slightly worse in the first group, decreasing from 42 to 22%, and being 29% for the new participants. This observation points out the difficulty linked to the interpretation of missense mutations itself rather than the lack of experience in quality controls.

As observed in the other complex diseases such as breast cancer, approached through EMQN schemes, the EQA scheme results emphasise that is it very important to have good background knowledge of the genes being tested to guarantee the reliability of genetic testing as part of the medical evaluation, especially as relevant and validated information is now available on free access international and national mutation databases (http://www.mmrmissense.net/).


We thank Shirley McQuaid, Kathleen Claes, Anna Krepelova, and Manuel Teixeira for their participation to the scheme assessments. We are also grateful to Outi Kamarainen and Rob Elles for their constant help in improving the management of the schemes.