| Title: |
Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants. |
| Authors: |
Loong, L; Cubuk, C; Choi, S; Allen, S; Torr, B; Garrett, A; Loveday, C; Durkie, M; Callaway, A; Burghel, GJ; Drummond, J; Robinson, R; Berry, IR; Wallace, A; Eccles, DM; Tischkowitz, M; Ellard, S; Ware, JS; Hanson, H; Turnbull, C; CanVIG-UK |
| Contributors: |
Pronin, Lucy Wai Yee; Choi, Subin; Allen, Sophie; Pemberton - Whiteley, Bethany; Garrett, Alice; Turnbull, Clare |
| Publisher Information: |
ELSEVIER SCIENCE INC |
| Publication Year: |
2022 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
CanVIG-UK |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; application/pdf |
| Language: |
English |
| ISSN: |
1530-0366; 1098-3600 |
| Relation: |
Genetics in medicine : official journal of the American College of Medical Genetics, 2021; https://repository.icr.ac.uk/handle/internal/5007 |
| DOI: |
10.1016/j.gim.2021.11.011 |
| Availability: |
https://doi.org/10.1016/j.gim.2021.11.011; https://repository.icr.ac.uk/handle/internal/5007 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.E1A24213 |
| Database: |
BASE |