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dc.contributor.authorLoong, L
dc.contributor.authorCubuk, C
dc.contributor.authorChoi, S
dc.contributor.authorAllen, S
dc.contributor.authorTorr, B
dc.contributor.authorGarrett, A
dc.contributor.authorLoveday, C
dc.contributor.authorDurkie, M
dc.contributor.authorCallaway, A
dc.contributor.authorBurghel, GJ
dc.contributor.authorDrummond, J
dc.contributor.authorRobinson, R
dc.contributor.authorBerry, IR
dc.contributor.authorWallace, A
dc.contributor.authorEccles, DM
dc.contributor.authorTischkowitz, M
dc.contributor.authorEllard, S
dc.contributor.authorWare, JS
dc.contributor.authorHanson, H
dc.contributor.authorTurnbull, C
dc.contributor.authorCanVIG-UK
dc.date.accessioned2022-02-10T12:39:24Z
dc.date.available2022-02-10T12:39:24Z
dc.date.issued2021-11-18
dc.identifier.citationGenetics in medicine : official journal of the American College of Medical Genetics, 2021en_US
dc.identifier.issn1098-3600
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5007
dc.identifier.eissn1530-0366en_US
dc.identifier.eissn1530-0366
dc.identifier.doi10.1016/j.gim.2021.11.011en_US
dc.identifier.doi10.1016/j.gim.2021.11.011
dc.description.abstractPURPOSE: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.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCanVIG-UKen_US
dc.titleQuantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-11-12
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1016/j.gim.2021.11.011en_US
rioxxterms.licenseref.startdate2021-11-18
dc.relation.isPartOfGenetics in medicine : official journal of the American College of Medical Geneticsen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorTurnbull, Clareen_US


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