Loong, Lucy 
ORCID: 0000-0002-5933-027X, Cubuk, Cankut ORCID: 0000-0003-4646-0849, Choi, Subin, Allen, Sophie, Torr, Beth, Garrett, Alice ORCID: 0000-0001-8942-283X, Loveday, Chey, Durkie, Miranda ORCID: 0000-0001-7071-7048, Callaway, Alison, Burghel, George J et al (show 11 more authors)
(2022)
Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.
Genetics in medicine : official journal of the American College of Medical Genetics, 24 (3).
pp. 552-563.
Abstract
<h4>Purpose</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CanVIG-UK, Humans, Genetic Predisposition to Disease, BRCA1 Protein, Codon, Mutation, Missense, MutS Homolog 2 Protein, Genetic Variation |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 28 Sep 2023 10:10 |
| Last Modified: | 28 Sep 2023 10:10 |
| DOI: | 10.1016/j.gim.2021.11.011 |
| Open Access URL: | https://doi.org/10.1016/j.gim.2021.11.011 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173152 |
Dimensions
Dimensions
