Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network

Abstract

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic–high risk and benign–no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease–gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that ‘national subspecialist multidisciplinary meetings’ (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.

From <b><i>BRCA1</i></b> to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

“…With these technological advances comes a separate and new set of challenges including accurate classification of the variants identified [96]. Equally important is ensuring that, for mutations detected in the mainstream setting, at-risk family members are offered testing for the familial PV where appropriate [97].…”

Translating RNA Splicing Analysis into Diagnosis and Therapy

“…Aside from the technical aspects of how to control for variable batch effects in sequencing and how to deal with tissue-specific splicing and splicing artefacts apparent in read mapping, a critical part of this will be the development of clinical guidelines relating to how splicing abnormalities should be interpreted in terms of their pathogenicity in variant classification. Initial attempts at such guidelines have been made in relation to cancer susceptibility genes but it is likely that a much more nuanced and perhaps experimentally evidenced approach will be needed in order to try to take account of the complexity of RNA metabolism and splice isoform regulation [123]. Beyond diagnostics, funding of translational research into therapeutic splicing manipulation will be key.…”

Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations

“…CanVIG-UK was established in 2017 as part of the UK-ACGS activity supporting adoption and dissemination of the ACMG framework for variant interpretation. 5 CanVIG-UK currently comprises >100 clinical scientists, clinical geneticists and genetic counsellors, with representation from each of the 25 Molecular Diagnostic Laboratories and Clinical Genetics Services of the UK (NHS) and Republic of Ireland. The group meets monthly to undertake multidisciplinary review and interpretation of problematic clinically detected variants.…”

“…3 Additional evidence elements not present in the original 2015 ACMG framework have been introduced in recent specifications of the framework by ClinGen expert groups, as well as the UK-ACGS and CanVIG-UK. [4][5][6][7][8][9] Frequently encountered within CanVIG-UK are variants for which there is uncertainty and inconsistency regarding the combination of multiple evidence elements, in particular those for which (1) the evidence elements available do not conform to any of the combinations specified in the original ACMG framework; (2) a proposed combination of evidence elements is of contentious legitimacy; and (3) there are conflicting evidence elements, that is, towards both pathogenicity and benignity.…”

“…Permissible and non-permissible combinations of concordant evidence elements (CanVIG-UK consensus) Co-usage permitted, provided that there is a schema predefining distinct data types used for each, thus preventing 'double counting' of phenotypic features (eg PP4 is applied for molecular/tumour assay data, indicating specificity at gene level); PS4 is applied at patient level, counting the strength of features in cases and the number of cases/families5 …”