Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling.

BACKGROUND: Nearly 15% of BRCA1 and BRCA2 DNA tests lead to the identification of Variants of Uncertain Significance (VUS). VUS are classified in the Netherlands according to the Bell system and it is current practice that class III VUS are communicated to counsellees, but not class II or lower VUS. Our aims were to investigate the utility of in silico characteristics in the classification of VUS and whether initial VUS classifications justify differences in communication protocols during counselling. METHODS: We classified 88 missense VUS in BRCA1 and BRCA2 on the basis of an in silico analysis and compared the classification of a subset of 60 VUS of which additional information including family, genetic and tumour data was available. RESULTS: VUS allocated to class III more frequently showed in silico indications of a deleterious effect than class II VUS. Of the 46 VUS assigned to class II by in silico analysis alone, nearly half were eventually recategorised as class I and 10% as class III when additional information was included. CONCLUSIONS: As in silico analysis alone is not always sufficient to unambiguously assign VUS to either class II or class III, we would argue that the prospect of obtaining additional information from a family should be given more weight during the decision process preceding the communication of a VUS test result. Research initiatives such as the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), which strive to combine diverse sources of information, will be valuable in aiding a definitive classification of a VUS.

Value-based healthcare in Lynch syndrome.

Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare has been introduced as an approach to the cost-effective delivery of measurable patient value over complete cycles of care. This requires all involved stakeholders to formulate and validate 'patient value' for Lynch syndrome, as well as to identify targets and associated costs. The aim of this study was to develop a value-based care model for Lynch syndrome that can determine patient value and associated costs, and to design a coordinated care pathway from existing guidelines. All specialists in our hospital involved in the management of LS patients evaluated the care delivered to these patients at their department and formulated outcome measures relevant to patient value. Patients were then invited to complete a questionnaire that assessed the importance of these measures on a scale of 1-10. Six high-value outcomes were identified: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaecologic examination/biopsy (5) the offer of psychological help and (6) registration with the Dutch Lynch syndrome registry. A total of 38 (59 %) out of 62 patients completed the questionnaire. The relevance of all outcomes was confirmed by the patients and mean scores varied from 7.2 to 9.9. Patients underscored the relevance of both proper patient education and the efficiency of surveillance during their care cycle. Value-based care delivery for Lynch syndrome includes the implementation of six parameters related to prevention and early detection of cancer, a short cycle time and registration to ensure continuation of care. Estimated costs are 3320 for the first cycle of care ( 3550 including gynaecologic surveillance) and approximately 720 per subsequent annual cycle ( 950 including gynaecologic surveillance).