Quantifying prediction of pathogenicity for within-codon concordance (PM5) using 7541 functional classifications of BRCA1 and MSH2 missense variants.
ACMG
Classification
Codon
PM5
Variant
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
04
08
2021
revised:
21
10
2021
accepted:
12
11
2021
pubmed:
16
12
2021
medline:
24
3
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
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. 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. 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. These analyses support the graded use of PM5, with potential to use it at higher evidence weighting where more stringent criteria are met.
Identifiants
pubmed: 34906453
pii: S1098-3600(21)05389-2
doi: 10.1016/j.gim.2021.11.011
pmc: PMC8896276
pii:
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Codon
0
MSH2 protein, human
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
552-563Subventions
Organisme : Medical Research Council
ID : MC_UP_1102/20
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 27223
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469/Z/15/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C61296/A27223
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/18/4/34215
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Investigateurs
S Samant
(S)
A Lucassen
(A)
A Znaczko
(A)
A Shaw
(A)
A Ansari
(A)
A Kumar
(A)
A Donaldson
(A)
A Murray
(A)
A Ross
(A)
A Taylor-Beadling
(A)
A Taylor
(A)
A Innes
(A)
A Brady
(A)
A Kulkarni
(A)
A-C Hogg
(AC)
A Ramsay Bowden
(AR)
A Hadonou
(A)
B Coad
(B)
B McIldowie
(B)
B Speight
(B)
B DeSouza
(B)
B Mullaney
(B)
C McKenna
(C)
C Brewer
(C)
C Olimpio
(C)
C Clabby
(C)
C Crosby
(C)
C Jenkins
(C)
C Armstrong
(C)
C Bowles
(C)
C Brooks
(C)
C Byrne
(C)
C Maurer
(C)
D Baralle
(D)
D Chubb
(D)
D Stobo
(D)
D Moore
(D)
D O'Sullivan
(D)
D Donnelly
(D)
D Randhawa
(D)
D Halliday
(D)
E Atkinson
(E)
E Baple
(E)
E Rauter
(E)
E Johnston
(E)
E Woodward
(E)
E Maher
(E)
E Sofianopoulou
(E)
E Petrides
(E)
F Lalloo
(F)
F McRonald
(F)
F Pelz
(F)
I Frayling
(I)
G Evans
(G)
G Corbett
(G)
G Rea
(G)
H Clouston
(H)
H Powell
(H)
H Williamson
(H)
H Carley
(H)
H J W Thomas
(HJW)
I Tomlinson
(I)
J Cook
(J)
J Hoyle
(J)
J Tellez
(J)
J Whitworth
(J)
J Williams
(J)
J Murray
(J)
J Campbell
(J)
J Tolmie
(J)
J Field
(J)
J Mason
(J)
J Burn
(J)
J Bruty
(J)
J Callaway
(J)
J Grant
(J)
J Del Rey Jimenez
(J)
J Pagan
(J)
J VanCampen
(J)
J Barwell
(J)
K Monahan
(K)
K Tatton-Brown
(K)
K-R Ong
(KR)
K Murphy
(K)
K Andrews
(K)
K Mokretar
(K)
K Cadoo
(K)
K Smith
(K)
K Baker
(K)
K Brown
(K)
K Reay
(K)
K McKay Bounford
(K)
K Bradshaw
(K)
K Russell
(K)
K Stone
(K)
K Snape
(K)
L Crookes
(L)
L Reed
(L)
L Taggart
(L)
L Yarram
(L)
L Cobbold
(L)
L Walker
(L)
L Walker
(L)
L Hawkes
(L)
L Busby
(L)
L Izatt
(L)
L Kiely
(L)
L Hughes
(L)
L Side
(L)
L Sarkies
(L)
K-L Greenhalgh
(KL)
M Shanmugasundaram
(M)
M Duff
(M)
M Bartlett
(M)
M Watson
(M)
M Owens
(M)
M Bradford
(M)
M Huxley
(M)
M Slean
(M)
M Ryten
(M)
M Smith
(M)
M Ahmed
(M)
N Roberts
(N)
C O'Brien
(C)
O Middleton
(O)
P Tarpey
(P)
P Logan
(P)
P Dean
(P)
P May
(P)
P Brace
(P)
R Tredwell
(R)
R Harrison
(R)
R Hart
(R)
R Kirk
(R)
R Martin
(R)
R Nyanhete
(R)
R Wright
(R)
R Martin
(R)
R Davidson
(R)
R Cleaver
(R)
S Talukdar
(S)
S Butler
(S)
J Sampson
(J)
S Ribeiro
(S)
S Dell
(S)
S Mackenzie
(S)
S Hegarty
(S)
S Albaba
(S)
S McKee
(S)
S Palmer-Smith
(S)
S Heggarty
(S)
S MacParland
(S)
S Greville-Heygate
(S)
S Daniels
(S)
S Prapa
(S)
S Abbs
(S)
S Tennant
(S)
S Hardy
(S)
S MacMahon
(S)
T McVeigh
(T)
T Foo
(T)
T Bedenham
(T)
T Cranston
(T)
T McDevitt
(T)
V Clowes
(V)
V Tripathi
(V)
V McConnell
(V)
N Woodwaer
(N)
Y Wallis
(Y)
Z Kemp
(Z)
G Mullan
(G)
L Pierson
(L)
L Rainey
(L)
C Joyce
(C)
A Timbs
(A)
A-M Reuther
(AM)
B Frugtniet
(B)
B DeSouza
(B)
C Husher
(C)
C Lawn
(C)
C Corbett
(C)
D Nocera-Jijon
(D)
D Reay
(D)
E Cross
(E)
F Ryan
(F)
H Lindsay
(H)
J Oliver
(J)
J Dring
(J)
J Spiers
(J)
J Harper
(J)
K Ciucias
(K)
L Connolly
(L)
M Tsang
(M)
R Brown
(R)
S Shepherd
(S)
S Begum
(S)
S Daniels
(S)
T Tadiso
(T)
T Linton-Willoughby
(T)
H Heppell
(H)
K Sahan
(K)
L Worrillow
(L)
Z Allen
(Z)
M Barlett
(M)
C Watt
(C)
M Hegarty
(M)
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of Interest The authors declare no conflicts of interest.
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