dc.contributor.author | Garrett, A | |
dc.contributor.author | Loveday, C | |
dc.contributor.author | King, L | |
dc.contributor.author | Butler, S | |
dc.contributor.author | Robinson, R | |
dc.contributor.author | Horton, C | |
dc.contributor.author | Yussuf, A | |
dc.contributor.author | Choi, S | |
dc.contributor.author | Torr, B | |
dc.contributor.author | Durkie, M | |
dc.contributor.author | Burghel, GJ | |
dc.contributor.author | Drummond, J | |
dc.contributor.author | Berry, I | |
dc.contributor.author | Wallace, A | |
dc.contributor.author | Callaway, A | |
dc.contributor.author | Eccles, D | |
dc.contributor.author | Tischkowitz, M | |
dc.contributor.author | Tatton-Brown, K | |
dc.contributor.author | Snape, K | |
dc.contributor.author | McVeigh, T | |
dc.contributor.author | Izatt, L | |
dc.contributor.author | Woodward, ER | |
dc.contributor.author | Burnichon, N | |
dc.contributor.author | Gimenez-Roqueplo, A-P | |
dc.contributor.author | Mazzarotto, F | |
dc.contributor.author | Whiffin, N | |
dc.contributor.author | Ware, J | |
dc.contributor.author | Hanson, H | |
dc.contributor.author | Pesaran, T | |
dc.contributor.author | LaDuca, H | |
dc.contributor.author | Buffet, A | |
dc.contributor.author | Maher, ER | |
dc.contributor.author | Turnbull, C | |
dc.contributor.author | Cancer Variant Interpretation Group UK (CanVIG-UK), | |
dc.date.accessioned | 2022-04-01T13:40:40Z | |
dc.date.available | 2022-04-01T13:40:40Z | |
dc.date.issued | 2022-01-01 | |
dc.identifier.citation | Genetics in medicine : official journal of the American College of Medical Genetics, 2022, 24 (1), pp. 41 - 50 | |
dc.identifier.issn | 1098-3600 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5064 | |
dc.identifier.eissn | 1530-0366 | |
dc.identifier.eissn | 1530-0366 | |
dc.identifier.doi | 10.1016/j.gim.2021.08.004 | |
dc.identifier.doi | 10.1016/j.gim.2021.08.004 | |
dc.description.abstract | PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity. | |
dc.format | Print-Electronic | |
dc.format.extent | 41 - 50 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER SCIENCE INC | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Cancer Variant Interpretation Group UK (CanVIG-UK) | |
dc.title | Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-08-10 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1016/j.gim.2021.08.004 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.relation.isPartOf | Genetics in medicine : official journal of the American College of Medical Genetics | |
pubs.issue | 1 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genetics Education & Quality Improvement | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/19/20 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Genetics Education & Quality Improvement | |
dc.contributor.icrauthor | Garrett, Alice | |
dc.contributor.icrauthor | Torr, Bethany | |
dc.contributor.icrauthor | McVeigh, Terri | |
dc.contributor.icrauthor | Turnbull, Clare | |