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2. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Brown, D., Willan, J., Taylor, S., Jones, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., O’Dubhshlaine, C., McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., Hayden, C., Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, and Turnbull, Clare

Published
2025
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3. The impact of inversions across 33,924 families with rare disease from a national genome sequencing project

Author

Pagnamenta, Alistair T., Yu, Jing, Walker, Susan, Noble, Alexandra J., Lord, Jenny, Dutta, Prasun, Hashim, Mona, Camps, Carme, Green, Hannah, Devaiah, Smrithi, Nashef, Lina, Parr, Jason, Fratter, Carl, Ibnouf Hussein, Rana, Lindsay, Sarah J., Lalloo, Fiona, Banos-Pinero, Benito, Evans, David, Mallin, Lucy, Waite, Adrian, Evans, Julie, Newman, Andrew, Allen, Zoe, Perez-Becerril, Cristina, Ryan, Gavin, Hart, Rachel, Taylor, John, Bedenham, Tina, Clement, Emma, Blair, Ed, Hay, Eleanor, Forzano, Francesca, Higgs, Jenny, Canham, Natalie, Majumdar, Anirban, McEntagart, Meriel, Lahiri, Nayana, Stewart, Helen, Smithson, Sarah, Calpena, Eduardo, Jackson, Adam, Banka, Siddharth, Titheradge, Hannah, McGowan, Ruth, Rankin, Julia, Shaw-Smith, Charles, Evans, D. Gareth, Burghel, George J., Smith, Miriam J., Anderson, Emily, Madhu, Rajesh, Firth, Helen, Ellard, Sian, Brennan, Paul, Anderson, Claire, Taupin, Doug, Rogers, Mark T., Cook, Jackie A., Durkie, Miranda, East, James E., Fowler, Darren, Wilson, Louise, Igbokwe, Rebecca, Gardham, Alice, Tomlinson, Ian, Baralle, Diana, Uhlig, Holm H., and Taylor, Jenny C.

Published
2024
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4. Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK)

Author

Loong, Lucy, Garrett, Alice, Allen, Sophie, Choi, Subin, Durkie, Miranda, Callaway, Alison, Drummond, James, Burghel, George J., Robinson, Rachel, Torr, Beth, Berry, Ian R., Wallace, Andrew J., Eccles, Diana M., Ellard, Sian, Baple, Emma, Evans, D. Gareth, Woodward, Emma R., Kulkarni, Anjana, Lalloo, Fiona, Tischkowitz, Marc, Lucassen, Anneke, Hanson, Helen, and Turnbull, Clare

Published
2022
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5. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., Hegarty, M., Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, and Turnbull, Clare

Published
2022
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6. Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD

Author

Garrett, Alice, Loveday, Chey, King, Laura, Butler, Samantha, Robinson, Rachel, Horton, Carrie, Yussuf, Amal, Choi, Subin, Torr, Beth, Durkie, Miranda, Burghel, George J., Drummond, James, Berry, Ian, Wallace, Andrew, Callaway, Alison, Eccles, Diana, Tischkowitz, Marc, Tatton-Brown, Katrina, Snape, Katie, McVeigh, Terri, Izatt, Louise, Woodward, Emma R., Burnichon, Nelly, Gimenez-Roqueplo, Anne-Paule, Mazzarotto, Francesco, Whiffin, Nicola, Ware, James, Hanson, Helen, Pesaran, Tina, LaDuca, Holly, Buffet, Alexandre, Maher, Eamonn R., and Turnbull, Clare

Published
2022
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8. Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.

Author

Ellard, Sian, Morgan, Sian, Wynn, Sarah L., Walker, Susan, Parrish, Andrew, Mein, Rachael, Juett, Ana, Joo Wook Ahn, Berry, Ian, Cassidy, Emma- Jane, Durkie, Miranda, Fish, Louise, Hall, Richard, Howard, Emma, Rankin, Julia, Wright, Caroline F., Deans, Zandra C., Scott, Richard H., Hill, Sue L., and Baple, Emma L.

Abstract

Purpose and scope The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. Methods of statement development A 1- day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. Results and conclusions We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources. [ABSTRACT FROM AUTHOR]

Published
2024
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9. The PS4- likelihood ratio calculator: flexible allocation of evidence weighting for case- control data in variant classification.

Author

Rowlands, Charlie F., Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Smith, Sheila Palmer, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, McVeigh, Terri P., Hanson, Helen, Whiffin, Nicola, Jones, Michael, and Turnbull, Clare

Abstract

Background The 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/ AMP) variant classification framework specifies that case- control observations can be scored as 'strong' evidence (PS4) towards pathogenicity. Methods We developed the PS4- likelihood ratio calculator (PS4- LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by prespecified OR thresholds. Model 1 represents the hypothesis of association between variant and phenotype (eg, OR≥5) and model 2 represents the hypothesis of non- association (eg, OR≤1). Results PS4- LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log- converted into log LR (evidence points). Using PS4- LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced data sets generated for more common phenotypes and smaller data sets more typical in very rare disease variant evaluation. Conclusion PS4- LRCalc enables flexible evidence quantitation on a continuous scale for observed case- control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey

Author

Allen, Sophie, primary, Loong, Lucy, additional, Garrett, Alice, additional, Torr, Bethany, additional, Durkie, Miranda, additional, Drummond, James, additional, Callaway, Alison, additional, Robinson, Rachel, additional, Burghel, George J, additional, Hanson, Helen, additional, Field, Joanne, additional, McDevitt, Trudi, additional, McVeigh, Terri P, additional, Bedenham, Tina, additional, Bowles, Christopher, additional, Bradshaw, Kirsty, additional, Brooks, Claire, additional, Butler, Samantha, additional, Del Rey Jimenez, Juan Carlos, additional, Hawkes, Lorraine, additional, Stinton, Victoria, additional, MacMahon, Suzanne, additional, Owens, Martina, additional, Palmer-Smith, Sheila, additional, Smith, Kenneth, additional, Tellez, James, additional, Valganon-Petrizan, Mikel, additional, Waskiewicz, Erik, additional, Yau, Michael, additional, Eccles, Diana M, additional, Tischkowitz, Marc, additional, Goel, Shilpi, additional, McRonald, Fiona, additional, Antoniou, Antonis C, additional, Morris, Eva, additional, Hardy, Steven, additional, and Turnbull, Clare, additional

Published
2023
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13. Recommendations for laboratory workflow that better support centralised amalgamation of genomic variant data: findings from CanVIG-UK national molecular laboratory survey.

Author

Allen, Sophie, Loong, Lucy, Garrett, Alice, Torr, Bethany, Durkie, Miranda, Drummond, James, Callaway, Alison, Robinson, Rachel, Burghel, George J., Hanson, Helen, Field, Joanne, McDevitt, Trudi, McVeigh, Terri P., Bedenham, Tina, Bowles, Christopher, Bradshaw, Kirsty, Brooks, Claire, Butler, Samantha, Del Rey Jimenez, Juan Carlos, and Hawkes, Lorraine

Abstract

Background National and international amalgamation of genomic data offers opportunity for research and audit, including analyses enabling improved classification of variants of uncertain significance. Review of individual-level data from National Health Service (NHS) testing of cancer susceptibility genes (2002-2023) submitted to the National Disease Registration Service revealed heterogeneity across participating laboratories regarding (1) the structure, quality and completeness of submitted data, and (2) the ease with which that data could be assembled locally for submission. Methods In May 2023, we undertook a closed online survey of 51 clinical scientists who provided consensus responses representing all 17 of 17 NHS molecular genetic laboratories in England and Wales which undertake NHS diagnostic analyses of cancer susceptibility genes. The survey included 18 questions relating to 'next-generation sequencing workflow' (11), 'variant classification' (3) and 'phenotypical context' (4). Results Widely differing processes were reported for transfer of variant data into their local LIMS (Laboratory Information Management System), for the formatting in which the variants are stored in the LIMS and which classes of variants are retained in the local LIMS. Differing local provisions and workflow for variant classifications were also reported, including the resources provided and the mechanisms by which classifications are stored. Conclusion The survey responses illustrate heterogeneous laboratory workflow for preparation of genomic variant data from local LIMS for centralised submission. Workflow is often labour-intensive and inefficient, involving multiple manual steps which introduce opportunities for error. These survey findings and adoption of the concomitant recommendations may support improvement in laboratory dataflows, better facilitating submission of data for central amalgamation. [ABSTRACT FROM AUTHOR]

Published
2024
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14. The Common PKD1 p.(Ile3167Phe) Variant Is Hypomorphic and Associated with Very Early Onset, Biallelic Polycystic Kidney Disease

Author

Durkie, Miranda, primary, Watson, Christopher M., additional, Winship, Peter, additional, Hogg, Anne-Cecile, additional, Nyanhete, Rodney, additional, Cooley, Sharon, additional, Valluru, Manoj K., additional, Shaw-Smith, Charles, additional, Bingham, Coralie, additional, Gilchrist, Mark, additional, Kenny, Janna, additional, Consortium, Genomics England Research, additional, and Ong, Albert C. M., additional

Published
2023
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16. UK recommendations for SDHA germline genetic testing and surveillance in clinical practice

Author

Hanson, Helen, Durkie, Miranda, Lalloo, Fiona, Izatt, Louise, McVeigh, Terri P., Cook, Jackie A., Brewer, Carole, Drummond, James, Cranston, Treena, Butler, Samantha, Casey, Ruth, Tan, Tricia, Morganstein, Daniel, Eccles, Diana M., Tischkowitz, Marc, Turnbull, Clare, Woodward, Emma Roisin, Maher, Eamonn R., Hanson, Helen, Durkie, Miranda, Lalloo, Fiona, Izatt, Louise, McVeigh, Terri P., Cook, Jackie A., Brewer, Carole, Drummond, James, Cranston, Treena, Butler, Samantha, Casey, Ruth, Tan, Tricia, Morganstein, Daniel, Eccles, Diana M., Tischkowitz, Marc, Turnbull, Clare, Woodward, Emma Roisin, and Maher, Eamonn R.

Abstract

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.

Published
2023

17. Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996–2020: development of a national resource of patient-level genomics laboratory records

Author

Loong, Lucy, primary, Huntley, Catherine, additional, McRonald, Fiona, additional, Santaniello, Francesco, additional, Pethick, Joanna, additional, Torr, Bethany, additional, Allen, Sophie, additional, Tulloch, Oliver, additional, Goel, Shilpi, additional, Shand, Brian, additional, Rahman, Tameera, additional, Luchtenborg, Margreet, additional, Garrett, Alice, additional, Barber, Richard, additional, Bedenham, Tina, additional, Bourn, David, additional, Bradshaw, Kirsty, additional, Brooks, Claire, additional, Bruty, Jonathan, additional, Burghel, George J, additional, Butler, Samantha, additional, Buxton, Chris, additional, Callaway, Alison, additional, Callaway, Jonathan, additional, Drummond, James, additional, Durkie, Miranda, additional, Field, Joanne, additional, Jenkins, Lucy, additional, McVeigh, Terri P, additional, Mountford, Roger, additional, Nyanhete, Rodney, additional, Petrides, Evgenia, additional, Robinson, Rachel, additional, Scott, Tracy, additional, Stinton, Victoria, additional, Tellez, James, additional, Wallace, Andrew J, additional, Yarram-Smith, Laura, additional, Sahan, Kate, additional, Hallowell, Nina, additional, Eccles, Diana M, additional, Pharoah, Paul, additional, Tischkowitz, Marc, additional, Antoniou, Antonis C, additional, Evans, D Gareth, additional, Lalloo, Fiona, additional, Norbury, Gail, additional, Morris, Eva, additional, Burn, John, additional, Hardy, Steven, additional, and Turnbull, Clare, additional

Published
2022
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18. UK recommendations for SDHA germline genetic testing and surveillance in clinical practice

Author

Hanson, Helen, Durkie, Miranda, Lalloo, Fiona, Izatt, Louise, McVeigh, Terri P, Cook, Jackie A, Brewer, Carole, Drummond, James, Butler, Samantha, Cranston, Treena, Casey, Ruth, Tan, Tricia, Morganstein, Daniel, Eccles, Diana M, Tischkowitz, Marc, Turnbull, Clare, Woodward, Emma Roisin, Maher, Eamonn R, UK Cancer Genetics Centres, Hanson, Helen [0000-0002-3303-8713], Izatt, Louise [0000-0003-1258-4843], Eccles, Diana M [0000-0002-9935-3169], Woodward, Emma Roisin [0000-0002-6297-2855], Maher, Eamonn R [0000-0002-6226-6918], and Apollo - University of Cambridge Repository

Subjects
genetic predisposition to disease, Paraganglioma, endocrinology, Electron Transport Complex II, Adrenal Gland Neoplasms, Humans, Genetic Testing, Pheochromocytoma, genetic counselling, Germ-Line Mutation, United Kingdom
Abstract

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.

Published
2022
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20. UK recommendations forSDHAgermline genetic testing and surveillance in clinical practice

Author

Hanson, Helen, primary, Durkie, Miranda, additional, Lalloo, Fiona, additional, Izatt, Louise, additional, McVeigh, Terri P, additional, Cook, Jackie A, additional, Brewer, Carole, additional, Drummond, James, additional, Butler, Samantha, additional, Cranston, Treena, additional, Casey, Ruth, additional, Tan, Tricia, additional, Morganstein, Daniel, additional, Eccles, Diana M, additional, Tischkowitz, Marc, additional, Turnbull, Clare, additional, Woodward, Emma Roisin, additional, and Maher, Eamonn R, additional

Published
2022
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21. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants

Author

Loong, Lucy, primary, Cubuk, Cankut, additional, Choi, Subin, additional, Allen, Sophie, additional, Torr, Beth, additional, Garrett, Alice, additional, Loveday, Chey, additional, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J., additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian R., additional, Wallace, Andrew, additional, Eccles, Diana M., additional, Tischkowitz, Marc, additional, Ellard, Sian, additional, Ware, James S., additional, Hanson, Helen, additional, Turnbull, Clare, additional, Samant, S., additional, Lucassen, A., additional, Znaczko, A., additional, Shaw, A., additional, Ansari, A., additional, Kumar, A., additional, Donaldson, A., additional, Murray, A., additional, Ross, A., additional, Taylor-Beadling, A., additional, Taylor, A., additional, Innes, A., additional, Brady, A., additional, Kulkarni, A., additional, Hogg, A.-C., additional, Bowden, A. Ramsay, additional, Hadonou, A., additional, Coad, B., additional, McIldowie, B., additional, Speight, B., additional, DeSouza, B., additional, Mullaney, B., additional, McKenna, C., additional, Brewer, C., additional, Olimpio, C., additional, Clabby, C., additional, Crosby, C., additional, Jenkins, C., additional, Armstrong, C., additional, Bowles, C., additional, Brooks, C., additional, Byrne, C., additional, Maurer, C., additional, Baralle, D., additional, Chubb, D., additional, Stobo, D., additional, Moore, D., additional, O'Sullivan, D., additional, Donnelly, D., additional, Randhawa, D., additional, Halliday, D., additional, Atkinson, E., additional, Baple, E., additional, Rauter, E., additional, Johnston, E., additional, Woodward, E., additional, Maher, E., additional, Sofianopoulou, E., additional, Petrides, E., additional, Lalloo, F., additional, McRonald, F., additional, Pelz, F., additional, Frayling, I., additional, Evans, G., additional, Corbett, G., additional, Rea, G., additional, Clouston, H., additional, Powell, H., additional, Williamson, H., additional, Carley, H., additional, Thomas, H.J.W., additional, Tomlinson, I., additional, Cook, J., additional, Hoyle, J., additional, Tellez, J., additional, Whitworth, J., additional, Williams, J., additional, Murray, J., additional, Campbell, J., additional, Tolmie, J., additional, Field, J., additional, Mason, J., additional, Burn, J., additional, Bruty, J., additional, Callaway, J., additional, Grant, J., additional, Del Rey Jimenez, J., additional, Pagan, J., additional, VanCampen, J., additional, Barwell, J., additional, Monahan, K., additional, Tatton-Brown, K., additional, Ong, K.-R., additional, Murphy, K., additional, Andrews, K., additional, Mokretar, K., additional, Cadoo, K., additional, Smith, K., additional, Baker, K., additional, Brown, K., additional, Reay, K., additional, McKay Bounford, K., additional, Bradshaw, K., additional, Russell, K., additional, Stone, K., additional, Snape, K., additional, Crookes, L., additional, Reed, L., additional, Taggart, L., additional, Yarram, L., additional, Cobbold, L., additional, Walker, L., additional, Hawkes, L., additional, Busby, L., additional, Izatt, L., additional, Kiely, L., additional, Hughes, L., additional, Side, L., additional, Sarkies, L., additional, Greenhalgh, K.-L., additional, Shanmugasundaram, M., additional, Duff, M., additional, Bartlett, M., additional, Watson, M., additional, Owens, M., additional, Bradford, M., additional, Huxley, M., additional, Slean, M., additional, Ryten, M., additional, Smith, M., additional, Ahmed, M., additional, Roberts, N., additional, O'Brien, C., additional, Middleton, O., additional, Tarpey, P., additional, Logan, P., additional, Dean, P., additional, May, P., additional, Brace, P., additional, Tredwell, R., additional, Harrison, R., additional, Hart, R., additional, Kirk, R., additional, Martin, R., additional, Nyanhete, R., additional, Wright, R., additional, Davidson, R., additional, Cleaver, R., additional, Talukdar, S., additional, Butler, S., additional, Sampson, J., additional, Ribeiro, S., additional, Dell, S., additional, Mackenzie, S., additional, Hegarty, S., additional, Albaba, S., additional, McKee, S., additional, Palmer-Smith, S., additional, Heggarty, S., additional, MacParland, S., additional, Greville-Heygate, S., additional, Daniels, S., additional, Prapa, S., additional, Abbs, S., additional, Tennant, S., additional, Hardy, S., additional, MacMahon, S., additional, McVeigh, T., additional, Foo, T., additional, Bedenham, T., additional, Cranston, T., additional, McDevitt, T., additional, Clowes, V., additional, Tripathi, V., additional, McConnell, V., additional, Woodwaer, N., additional, Wallis, Y., additional, Kemp, Z., additional, Mullan, G., additional, Pierson, L., additional, Rainey, L., additional, Joyce, C., additional, Timbs, A., additional, Reuther, A.-M., additional, Frugtniet, B., additional, Husher, C., additional, Lawn, C., additional, Corbett, C., additional, Nocera-Jijon, D., additional, Reay, D., additional, Cross, E., additional, Ryan, F., additional, Lindsay, H., additional, Oliver, J., additional, Dring, J., additional, Spiers, J., additional, Harper, J., additional, Ciucias, K., additional, Connolly, L., additional, Tsang, M., additional, Brown, R., additional, Shepherd, S., additional, Begum, S., additional, Tadiso, T., additional, Linton-Willoughby, T., additional, Heppell, H., additional, Sahan, K., additional, Worrillow, L., additional, Allen, Z., additional, Barlett, M., additional, Watt, C., additional, and Hegarty, M., additional

Published
2022
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23. Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)

Author

Garrett, Alice, Allen, Sophie, Durkie, Miranda, Burghel, George J., Robinson, Rachel, Callaway, Alison, Field, Joanne, Frugtniet, Bethan, Palmer-Smith, Sheila, Grant, Jonathan, Pagan, Judith, McDevitt, Trudi, Rowlands, Charlie F., McVeigh, Terri, Hanson, Helen, Turnbull, Clare, Turnbull, C., Garrett, A., Loong, L., Choi, S., Torr, B., Allen, S., Durkie, M., Callaway, A., Drummond, J., Burghel, G.J., Robinson, R., Berry, I.R., Wallace, A.J., Eccles, D.M., Tischkowitz, M., Ellard, S., Hanson, H., Baple, E., Evans, D.G., Woodward, E., Lalloo, F., Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Rauter, E., Johnston, E., Maher, E., Sofianopoulou, E., Petrides, E., McRonald, F., Pelz, F., Frayling, I., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Watt, C., Hegarty, M., Mitchell, R., Coles, R., Nickless, G., Cojocaru, E., Doal, I., Sava, F., McCarthy, C., Jeeneea, R., Goudie, D., McConachie, M., Botosneanu, S., Kavanaugh, G., Russell, K., Sherlaw, C., Tsoulaki, O., Forde, C., Petley, E., Jones, A.-B., Oprych, K., Pryde, S., Hyder, Z., Elkhateeb, N., Braham, R., Hanington, L., Huntley, C., Irving, R., Sadan, A., Ramos, M., Elliot, C., Wren, D., Lobo, D., McLean, J., May, D., Kearney, L., Campbell, T., Asakura, K., Alwadi, L., O’Shea, R., Gabriel, J., Chiecchio, L., Bowman, P., Sutton, L.A., Walsh, C., Cloke, V., Ucanok, D., Davies, J., Pleasance, B., Maguire, E., Whaite, A., Best, S., Westbury, S., Logan, A., Navarajasegaran, D., Bench, A., Wightman, P., Cartwright, A., Higgs, E., J.Bott, Whitehouse, H., Stevens, J., Martin, D., Dunlop, J., Thomas, S., Sau, C., Farndon, S., Coleman, N., Angelini, P., Duff, M., Massey, H., Rowlands, C., Garcia-Petit, C., Gillespie, K., Alder, A., Middleton, E., Cassidy, C., Orfali, N., Webb, A., Luharia, A., Walker, N., Charlton, J., Andreou, A., Peddie, J., Khan, M., Wilkinson, L., Bezuidenhout, H., Edis, M., Callard, A., Ostrowski, P., Moverley, P., Bean, K., Dunne, A., Moleirinho, A., Waller, S., Cox, K., Greensmith, L., Brittle, A., Gossan, N., Freestone, L., Shak, C., Langford, T., Clinch, Y., Livesey, H., Borland, S., Joshi, A., Wall, K., Whitworth, A., Wilsdon, A., Edgerley, K., Pugh, S., Chrysochoidi, N., Mutch, S., McMullan, C., Johnston, Y., Muraru, M., May, A., Begum, R., Smith, C., Patel, R., Bhatnagar, I., Taylor, A., Brown, D., Willan, J., Taylor, S., Jones, K., Cox, K., Ramsden, C., Taiwo, O., Jaudzemaite, J., Sharmin, R., Young, L., O’Dubhshlaine, C., McSorley, L., Rodriguez, I. Abreu, Lillis, S., Alexopoulos, P., Mortensson, E., Kingham, L., Moore, R., Kosicka-Slawinska, M., Aslam, S., Wells, R., Carter, A., Warren, H., Rolf, E., Reed, H., Pearce, L., Lock, D., Ali, F., Kolozi, A., White, N., Wood, D., and Hayden, C.

Abstract

Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.

Published
2025
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25. Harnessing national pan-laboratory data for accurate quantitation of PS4 in cancer susceptibility genes: Cancer Variant Interpretation Group UK (CanVIG-UK)

Author

Garrett, Alice, primary, Loveday, Chey, additional, Durkie, Miranda, additional, Burghel, George, additional, Drummond, James, additional, Robinson, Rachel, additional, Berry, Ian, additional, Wallace, Andrew, additional, King, Laura, additional, Choi, Subin, additional, Soufianopoulou, Eleni, additional, McRonald, Fiona, additional, Santaniello, Francesco, additional, Burn, John, additional, Rashbass, Jem, additional, Hardy, Steven, additional, Eccles, Diana, additional, Tischkowitz, Marc, additional, and Turnbull, Clare, additional

Published
2021
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26. Quantitative evidence evaluation for singleton rare missense variants in rare distinctive adult-onset phenotypes: the exemplar of SDHB and SDHD

Author

King, Laura, primary, Loveday, Chey, additional, Garrett, Alice, additional, Butler, Samantha, additional, Robinson, Rachel, additional, Maher, Eamonn, additional, Buffet, Alexandre, additional, Burnichon, Nelly, additional, Gimenez-Roqueplo, Anne-Paule, additional, Choi, Subin, additional, Durkie, Miranda, additional, Burghel, George, additional, Drummond, James, additional, Berry, Ian, additional, Wallace, Andrew, additional, Woodward, Emma, additional, Izatt, Louise, additional, Tischkowitz, Marc, additional, Whiffin, Nicky, additional, Ware, James, additional, Hanson, Helen, additional, and Turnbull, Clare, additional

Published
2021
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27. A genetic study of Wilson’s disease in the United Kingdom

Author

Coffey, Alison J., Durkie, Miranda, Hague, Stephen, McLay, Kirsten, Emmerson, Jennifer, Lo, Christine, Klaffke, Stefanie, Joyce, Christopher J., Dhawan, Anil, Hadzic, Nedim, Mieli-Vergani, Giorgina, Kirk, Richard, Elizabeth Allen, K., Nicholl, David, Wong, Siew, Griffiths, William, Smithson, Sarah, Giffin, Nicola, Taha, Ali, Connolly, Sally, Gillett, Godfrey T., Tanner, Stuart, Bonham, Jim, Sharrack, Basil, Palotie, Aarno, Rattray, Magnus, Dalton, Ann, and Bandmann, Oliver

Published
2013
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28. Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996–2020: development of a national resource of patient-level genomics laboratory records

Author

Loong, Lucy, Huntley, Catherine, McRonald, Fiona, Santaniello, Francesco, Pethick, Joanna, Torr, Bethany, Allen, Sophie, Tulloch, Oliver, Goel, Shilpi, Shand, Brian, Rahman, Tameera, Luchtenborg, Margreet, Garrett, Alice, Barber, Richard, Bedenham, Tina, Bourn, David, Bradshaw, Kirsty, Brooks, Claire, Bruty, Jonathan, Burghel, George J, Butler, Samantha, Buxton, Chris, Callaway, Alison, Callaway, Jonathan, Drummond, James, Durkie, Miranda, Field, Joanne, Jenkins, Lucy, McVeigh, Terri P, Mountford, Roger, Nyanhete, Rodney, Petrides, Evgenia, Robinson, Rachel, Scott, Tracy, Stinton, Victoria, Tellez, James, Wallace, Andrew J, Yarram-Smith, Laura, Sahan, Kate, Hallowell, Nina, Eccles, Diana M, Pharoah, Paul, Tischkowitz, Marc, Antoniou, Antonis C, Evans, D Gareth, Lalloo, Fiona, Norbury, Gail, Morris, Eva, Burn, John, Hardy, Steven, and Turnbull, Clare

Abstract

ObjectiveTo describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories.DesignLaboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years’ missing data.ResultsIndividual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed.ConclusionThe NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Published
2023
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29. UK recommendations for SDHAgermline genetic testing and surveillance in clinical practice

Author

Hanson, Helen, Durkie, Miranda, Lalloo, Fiona, Izatt, Louise, McVeigh, Terri P, Cook, Jackie A, Brewer, Carole, Drummond, James, Butler, Samantha, Cranston, Treena, Casey, Ruth, Tan, Tricia, Morganstein, Daniel, Eccles, Diana M, Tischkowitz, Marc, Turnbull, Clare, Woodward, Emma Roisin, and Maher, Eamonn R

Abstract

SDHApathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHAPGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHAPGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHAPGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHAPGV carriers will be identified in patients with tumours not strongly associated with SDHA,or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHAworking group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHAPGV carriers in clinical practice.

Published
2023
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30. Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations

Author

Garrett, Alice, primary, Durkie, Miranda, additional, Callaway, Alison, additional, Burghel, George J, additional, Robinson, Rachel, additional, Drummond, James, additional, Torr, Bethany, additional, Cubuk, Cankut, additional, Berry, Ian R, additional, Wallace, Andrew J, additional, Ellard, Sian, additional, Eccles, Diana M, additional, Tischkowitz, Marc, additional, Hanson, Helen, additional, and Turnbull, Clare, additional

Published
2020
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31. Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national specialist multi-disciplinary genomics forum

Author

Garrett, Alice, Callaway, Alison, Durkie, Miranda, Cubuk, Cankut, Alikian, Mary, Burghel, George, Robinson, Rachel, Izatt, Louise, Talukdar, Sabrina, Side, Lucy E., Cranston, Treena, Palmer-Smith, Sheila, Baralle, Diana, Berry, Ian R., Norbury, G., Eccles, Diana, Ellard, Sian, Lalloo, Fiona, Evans, D. Gareth, Woodward, Emma, Tischowitz, Marc, Hanson, Helen, and Turnbull, Clare

Abstract

The purpose of CanVIG-UK (Cancer Variant Interpretation Group UK) is to advance outcomes for patients by improving the accuracy and consistency of interpretation of variants in Cancer Susceptibility genes across the UK clinical and diagnostic laboratory communities (hereafter termed the UK clinical-laboratory community). CanVIG-UK currently comprises >100 members including clinical and laboratory representation from each of the 25 Molecular Diagnostic Laboratories and Clinical Genetics Services of the UK and ROI. This group comprises roughly equal proportions of clinical scientists and clinical geneticists, with two thirds work exclusively or predominantly in cancer genetics

Published
2020

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

Author

Garrett, Alice, primary, Callaway, Alison, additional, Durkie, Miranda, additional, Cubuk, Cankut, additional, Alikian, Mary, additional, Burghel, George J, additional, Robinson, Rachel, additional, Izatt, Louise, additional, Talukdar, Sabrina, additional, Side, Lucy, additional, Cranston, Treena, additional, Palmer-Smith, Sheila, additional, Baralle, Diana, additional, Berry, Ian R, additional, Drummond, James, additional, Wallace, Andrew J, additional, Norbury, Gail, additional, Eccles, Diana M, additional, Ellard, Sian, additional, Lalloo, Fiona, additional, Evans, D Gareth, additional, Woodward, Emma, additional, Tischkowitz, Marc, additional, Hanson, Helen, additional, and Turnbull, Clare, additional

Published
2020
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33. Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1and MSH2missense variants

Author

Loong, Lucy, Cubuk, Cankut, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice, Loveday, Chey, Durkie, Miranda, Callaway, Alison, Burghel, George J., Drummond, James, Robinson, Rachel, Berry, Ian R., Wallace, Andrew, Eccles, Diana M., Tischkowitz, Marc, Ellard, Sian, Ware, James S., Hanson, Helen, Turnbull, Clare, Samant, S., Lucassen, A., Znaczko, A., Shaw, A., Ansari, A., Kumar, A., Donaldson, A., Murray, A., Ross, A., Taylor-Beadling, A., Taylor, A., Innes, A., Brady, A., Kulkarni, A., Hogg, A.-C., Bowden, A. Ramsay, Hadonou, A., Coad, B., McIldowie, B., Speight, B., DeSouza, B., Mullaney, B., McKenna, C., Brewer, C., Olimpio, C., Clabby, C., Crosby, C., Jenkins, C., Armstrong, C., Bowles, C., Brooks, C., Byrne, C., Maurer, C., Baralle, D., Chubb, D., Stobo, D., Moore, D., O'Sullivan, D., Donnelly, D., Randhawa, D., Halliday, D., Atkinson, E., Baple, E., Rauter, E., Johnston, E., Woodward, E., Maher, E., Sofianopoulou, E., Petrides, E., Lalloo, F., McRonald, F., Pelz, F., Frayling, I., Evans, G., Corbett, G., Rea, G., Clouston, H., Powell, H., Williamson, H., Carley, H., Thomas, H.J.W., Tomlinson, I., Cook, J., Hoyle, J., Tellez, J., Whitworth, J., Williams, J., Murray, J., Campbell, J., Tolmie, J., Field, J., Mason, J., Burn, J., Bruty, J., Callaway, J., Grant, J., Del Rey Jimenez, J., Pagan, J., VanCampen, J., Barwell, J., Monahan, K., Tatton-Brown, K., Ong, K.-R., Murphy, K., Andrews, K., Mokretar, K., Cadoo, K., Smith, K., Baker, K., Brown, K., Reay, K., McKay Bounford, K., Bradshaw, K., Russell, K., Stone, K., Snape, K., Crookes, L., Reed, L., Taggart, L., Yarram, L., Cobbold, L., Walker, L., Walker, L., Hawkes, L., Busby, L., Izatt, L., Kiely, L., Hughes, L., Side, L., Sarkies, L., Greenhalgh, K.-L., Shanmugasundaram, M., Duff, M., Bartlett, M., Watson, M., Owens, M., Bradford, M., Huxley, M., Slean, M., Ryten, M., Smith, M., Ahmed, M., Roberts, N., O'Brien, C., Middleton, O., Tarpey, P., Logan, P., Dean, P., May, P., Brace, P., Tredwell, R., Harrison, R., Hart, R., Kirk, R., Martin, R., Nyanhete, R., Wright, R., Martin, R., Davidson, R., Cleaver, R., Talukdar, S., Butler, S., Sampson, J., Ribeiro, S., Dell, S., Mackenzie, S., Hegarty, S., Albaba, S., McKee, S., Palmer-Smith, S., Heggarty, S., MacParland, S., Greville-Heygate, S., Daniels, S., Prapa, S., Abbs, S., Tennant, S., Hardy, S., MacMahon, S., McVeigh, T., Foo, T., Bedenham, T., Cranston, T., McDevitt, T., Clowes, V., Tripathi, V., McConnell, V., Woodwaer, N., Wallis, Y., Kemp, Z., Mullan, G., Pierson, L., Rainey, L., Joyce, C., Timbs, A., Reuther, A.-M., Frugtniet, B., DeSouza, B., Husher, C., Lawn, C., Corbett, C., Nocera-Jijon, D., Reay, D., Cross, E., Ryan, F., Lindsay, H., Oliver, J., Dring, J., Spiers, J., Harper, J., Ciucias, K., Connolly, L., Tsang, M., Brown, R., Shepherd, S., Begum, S., Daniels, S., Tadiso, T., Linton-Willoughby, T., Heppell, H., Sahan, K., Worrillow, L., Allen, Z., Barlett, M., Watt, C., and Hegarty, M.

Abstract

Conditions and thresholds applied for evidence weighting of within-codon concordance (PM5) for pathogenicity vary widely between laboratories and expert groups. Because of the sparseness of available clinical classifications, there is little evidence for variation in practice.

Published
2022
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34. Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHBand SDHD

Author

Garrett, Alice, Loveday, Chey, King, Laura, Butler, Samantha, Robinson, Rachel, Horton, Carrie, Yussuf, Amal, Choi, Subin, Torr, Beth, Durkie, Miranda, Burghel, George J., Drummond, James, Berry, Ian, Wallace, Andrew, Callaway, Alison, Eccles, Diana, Tischkowitz, Marc, Tatton-Brown, Katrina, Snape, Katie, McVeigh, Terri, Izatt, Louise, Woodward, Emma R., Burnichon, Nelly, Gimenez-Roqueplo, Anne-Paule, Mazzarotto, Francesco, Whiffin, Nicola, Ware, James, Hanson, Helen, Pesaran, Tina, LaDuca, Holly, Buffet, Alexandre, Maher, Eamonn R., and Turnbull, Clare

Abstract

The weight of the evidence to attach to observation of a novel rare missense variant in SDHBor SDHDin individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain.

Published
2022
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35. Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations.

Author

Garrett, Alice, Durkie, Miranda, Callaway, Alison, Burghel, George J., Robinson, Rachel, Drummond, James, Torr, Bethany, Cubuk, Cankut, Berry, Ian R., Wallace, Andrew J., Ellard, Sian, Eccles, Diana M., Tischkowitz, Marc, Hanson, Helen, and Turnbull, Clare

Abstract

Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical 'exponent score' (2) new combinations of evidence elements constituting likely pathogenic' and 'pathogenic' classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity. [ABSTRACT FROM AUTHOR]

Published
2021
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36. Biallelic inheritance of hypomorphic PKD1variants is highly prevalent in very early onset polycystic kidney disease

Author

Durkie, Miranda, Chong, Jiehan, Valluru, Manoj K., Harris, Peter C., and Ong, Albert C.M.

Abstract

To investigate the prevalence of biallelic PKD1and PKD2variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020).

Published
2021
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42. A study of Wilson disease mutations in Britain

Author

Curtis, Diana, primary, Durkie, Miranda, additional, Balac (Morris), Pauline, additional, Sheard, Donna, additional, Goodeve, Anne, additional, Peake, Ian, additional, Quarrell, Oliver, additional, and Tanner, Stuart, additional

Published
1999
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43. Minimal residual disease detection in childhood Acute Lymphoblastic Leukaemia: preliminary results from the ALL2003 clinical trial.

Author

Durkie, Miranda, M. Habib, Miranda, Holden, J., Harrett-Williams, R., Wright, G., Oldfield, N., Scoular, J., Evans, P., Westgate, E., Hancock, J., and Goulden, N.

Subjects
CLINICAL trials, DISEASES, POLYMERASE chain reaction, DISEASE relapse, DRUG therapy
Abstract

Focuses on the clinical trials to established to explore the use of minimal residual disease (MRD). Aim of the exercise to stratify patients into different treatment therapies; Use of polymerase chain reaction to quantitate MRD; Likelihood of relapse by half of patients in the lowest treatment regimes; Suggestion for chemotherapy for patients with low MRD; Effectiveness of MRD detection as a prognostic tool.

Published
2003

44. OP052 - Harnessing national pan-laboratory data for accurate quantitation of PS4 in cancer susceptibility genes: Cancer Variant Interpretation Group UK (CanVIG-UK).

Author

Garrett, Alice, Loveday, Chey, Durkie, Miranda, Burghel, George, Drummond, James, Robinson, Rachel, Berry, Ian, Wallace, Andrew, King, Laura, Choi, Subin, Soufianopoulou, Eleni, McRonald, Fiona, Santaniello, Francesco, Burn, John, Rashbass, Jem, Hardy, Steven, Eccles, Diana, Tischkowitz, Marc, and Turnbull, Clare

Subjects
*CANCER genes, CANCER susceptibility
Published
2021
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45. OP051 - Quantitative evidence evaluation for singleton rare missense variants in rare distinctive adult-onset phenotypes: the exemplar of SDHB and SDHD.

Author

King, Laura, Loveday, Chey, Garrett, Alice, Butler, Samantha, Robinson, Rachel, Maher, Eamonn, Buffet, Alexandre, Burnichon, Nelly, Gimenez-Roqueplo, Anne-Paule, Choi, Subin, Durkie, Miranda, Burghel, George, Drummond, James, Berry, Ian, Wallace, Andrew, Woodward, Emma, Izatt, Louise, Tischkowitz, Marc, Whiffin, Nicky, and Ware, James

Subjects
*PHENOTYPES, *EVIDENCE
Published
2021
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46. Whole Genome Sequencing to Identify Novel Germline Fumarate Hydratase Mutation in Child With Bilateral Renal Cell Carcinoma.

Author

Kershaw C, Demain L, Baker E, Burghel G, Durkie M, Forde C, Makin G, Cheesman E, Warren A, Gokhale D, Schlecht H, Maher E, Oliveira P, and Woodward E

Abstract

An 11-year-old presented with bilateral renal cell carcinoma (RCC) with FH-deficient RCC confirmed by immunohistochemistry. WGS confirmed no coding variants but identified a rare intronic variant in FH (c.1391-269A>G). We illustrate how combined pathological and genomic investigations enabled a precise diagnosis of the underlying cause of an ultra-rare clinical presentation., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2025
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47. UK recommendations for SDHA germline genetic testing and surveillance in clinical practice.

Author

Hanson H, Durkie M, Lalloo F, Izatt L, McVeigh TP, Cook JA, Brewer C, Drummond J, Butler S, Cranston T, Casey R, Tan T, Morganstein D, Eccles DM, Tischkowitz M, Turnbull C, Woodward ER, and Maher ER

Subjects
Humans, Genetic Testing, Germ-Line Mutation genetics, United Kingdom, Genetic Predisposition to Disease, Electron Transport Complex II genetics, Paraganglioma genetics, Pheochromocytoma genetics, Adrenal Gland Neoplasms genetics
Abstract

SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice., Competing Interests: Competing interests: RC has received speakers' honoraria from Novartis and Ipsen; DM has received speakers' honoraria from Roche and MSD and speakers' honoraria and consulting fees from Bristol Myers Squib., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Published
2023
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