dc.contributor.author | Loong, L | |
dc.contributor.author | Cubuk, C | |
dc.contributor.author | Choi, S | |
dc.contributor.author | Allen, S | |
dc.contributor.author | Torr, B | |
dc.contributor.author | Garrett, A | |
dc.contributor.author | Loveday, C | |
dc.contributor.author | Durkie, M | |
dc.contributor.author | Callaway, A | |
dc.contributor.author | Burghel, GJ | |
dc.contributor.author | Drummond, J | |
dc.contributor.author | Robinson, R | |
dc.contributor.author | Berry, IR | |
dc.contributor.author | Wallace, A | |
dc.contributor.author | Eccles, DM | |
dc.contributor.author | Tischkowitz, M | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Ware, JS | |
dc.contributor.author | Hanson, H | |
dc.contributor.author | Turnbull, C | |
dc.contributor.author | CanVIG-UK, | |
dc.date.accessioned | 2022-02-10T12:39:24Z | |
dc.date.available | 2022-02-10T12:39:24Z | |
dc.date.issued | 2021-11-18 | |
dc.identifier.citation | Genetics in medicine : official journal of the American College of Medical Genetics, 2021 | |
dc.identifier.issn | 1098-3600 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5007 | |
dc.identifier.eissn | 1530-0366 | |
dc.identifier.eissn | 1530-0366 | |
dc.identifier.doi | 10.1016/j.gim.2021.11.011 | |
dc.identifier.doi | 10.1016/j.gim.2021.11.011 | |
dc.description.abstract | PURPOSE: 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. METHODS: We used as a truthset 7541 dichotomous functional classifications of BRCA1 and MSH2, spanning 311 codons of BRCA1 and 918 codons of MSH2, generated from large-scale functional assays that have been shown to correlate excellently with clinical classifications. We assessed PM5 at 5 stringencies with incorporation of 8 in silico tools. For each analysis, we quantified a positive likelihood ratio (pLR, true positive rate/false positive rate), the predictive value of PM5-lookup in ClinVar compared with the functional truthset. RESULTS: pLR was 16.3 (10.6-24.9) for variants for which there was exactly 1 additional colocated deleterious variant on ClinVar, and the variant under examination was equally or more damaging when analyzed using BLOSUM62. pLR was 71.5 (37.8-135.3) for variants for which there were 2 or more colocated deleterious ClinVar variants, and the variant under examination was equally or more damaging than at least 1 colocated variant when analyzed using BLOSUM62. CONCLUSION: These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER SCIENCE INC | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | CanVIG-UK | |
dc.title | Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-11-12 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1016/j.gim.2021.11.011 | |
rioxxterms.licenseref.startdate | 2021-11-18 | |
dc.relation.isPartOf | Genetics in medicine : official journal of the American College of Medical Genetics | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Published | |
pubs.embargo.terms | Not known | |
dc.contributor.icrauthor | Pronin, Lucy Wai Yee | |
dc.contributor.icrauthor | Allen, Sophie | |
dc.contributor.icrauthor | Pemberton - Whiteley, Bethany | |
dc.contributor.icrauthor | Garrett, Alice | |
dc.contributor.icrauthor | Turnbull, Clare | |