Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.
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Date
2021-11-18ICR Author
Author
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,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
CanVIG-UK
Language
eng
Date accepted
2021-11-12
License start date
2021-11-18
Citation
Genetics in medicine : official journal of the American College of Medical Genetics, 2021
Publisher
ELSEVIER SCIENCE INC