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@ARTICLE{Davidson:292080,
author = {A. L. Davidson and K. Michailidou and M. T. Parsons and C.
Fortuno and M. K. Bolla and Y. Wang and J. Dennis and M.
Naven and M. Abubakar and T. U. Ahearn and M. R. Alonso and
I. L. Andrulis and A. C. Antoniou and P. Auvinen and S.
Behrens$^*$ and M. A. Bermisheva and N. V. Bogdanova and S.
E. Bojesen and T. Brüning and H. J. Byers and N. J. Camp
and A. Campbell and J. E. Castelao and M. H. Cessna and J.
Chang-Claude$^*$ and S. J. Chanock and G. Chenevix-Trench
and J. M. Collée and K. Czene and T. Dörk and M. Eriksson
and D. G. Evans and P. A. Fasching and J. D. Figueroa and H.
Flyger and M. Gago-Dominguez and M. García-Closas and G.
Glendon and A. González-Neira and F. Grassmann and J.
Gronwald and P. Guénel and A. Hadjisavvas and L. Haeberle
and P. Hall and U. Hamann$^*$ and M. Hartman and P. J. Ho
and M. J. Hooning and R. Hoppe and A. Howell and A.
Jakubowska and E. K. Khusnutdinova and V. N. Kristensen and
J. Li and J. Lim and A. Lindblom and J. Liu and A.
Lophatananon and A. Mannermaa and D. A. Mavroudis and A. R.
Mensenkamp and R. L. Milne and K. R. Muir and W. G. Newman
and N. Obi and M. I. Panayiotidis and S. K. Park and T.-W.
Park-Simon and P. Peterlongo and P. Radice and M. U. Rashid
and V. Rhenius and E. Saloustros and E. J. Sawyer and M. K.
Schmidt and P. Seibold$^*$ and M. Shah and M. C. Southey and
S. H. Teo and I. Tomlinson and D. Torres$^*$ and T. Truong
and I. van de Beek and A. H. van der Hout and C. C. Wendt
and A. M. Dunning and P. D. P. Pharoah and P. Devilee and D.
F. Easton and P. A. James and A. B. Spurdle},
collaboration = {NBCS Collaborators and k. Investigators},
othercontributors = {K. K. Sahlberg and A.-L. Børresen-Dale and I. T. Gram and
K. S. Olsen and O. Engebråten and B. Naume and J. Geisler
and Osbreac and G. I. Grenaker Alnæs and D. Amor and L.
Andrews and Y. Antill and R. Balleine and J. Beesley and I.
Bennett and M. Bogwitz and S. Bodek and L. Botes and M.
Brennan and M. Brown and M. Buckley and J. Burke and P.
Butow and L. Caldon and I. Campbell and M. Cao and A.
Chakrabarti and D. Chauhan and M. Chauhan and A. Christian
and P. Cohen and A. Colley and A. Crook and J. Cui and E.
Courtney and M. Cummings and S.-J. Dawson and A. deFazio and
M. Delatycki and R. Dickson and J. Dixon and S. Edwards and
G. Farshid and A. Fellows and G. Fenton and M. Field and J.
Flanagan and P. Fong and L. Forrest and S. Fox and J. French
and M. Friedlander and C. Gaff and M. Gattas and P. George
and S. Greening and M. Harris and S. Hart and P. Harraka and
N. Hayward and J. Hopper and C. Hoskins and C. Hunt and M.
Jenkins and A. Kidd and J. Kirk and J. Koehler and J.
Kollias and S. Lakhani and M. Lawrence and J. Lee and S. Li
and G. Lindeman and J. Lippey and L. Lipton and L. Lobb and
S. Loi and G. Mann and D. Marsh and S. A. McLachlan and B.
Meiser and S. Nightingale and S. O'Connell and S. O'Sullivan
and D. G. Ortega and N. Pachter and J.-M. Pang and G. Pathak
and B. Patterson and A. Pearn and K. Phillips and E. Pieper
and S. Ramus and E. Rickard and A. Ragunathan and B.
Robinson and M. Saleh and A. Skandarajah and E. Salisbury
and C. Saunders and J. Saunus and P. Savas and R. Scott and
C. Scott and A. Sexton and J. Shaw and A. Shelling and S.
Srinivasa and P. Simpson and J. Taylor and R. Taylor and H.
Thorne and A. Trainer and K. Tucker and J. Visvader and L.
Walker and R. Williams and I. Winship and M. A. Young and M.
Zaheed},
title = {{C}o-observation of germline pathogenic variants in breast
cancer predisposition genes: {R}esults from analysis of the
{BRIDGES} sequencing dataset.},
journal = {The American journal of human genetics},
volume = {111},
number = {9},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DKFZ-2024-01588},
pages = {2059-2069},
year = {2024},
note = {2024 Sep 5;111(9):2059-2069},
abstract = {Co-observation of a gene variant with a pathogenic variant
in another gene that explains the disease presentation has
been designated as evidence against pathogenicity for
commonly used variant classification guidelines. Multiple
variant curation expert panels have specified, from
consensus opinion, that this evidence type is not applicable
for the classification of breast cancer predisposition gene
variants. Statistical analysis of sequence data for 55,815
individuals diagnosed with breast cancer from the BRIDGES
sequencing project was undertaken to formally assess the
utility of co-observation data for germline variant
classification. Our analysis included expected
loss-of-function variants in 11 breast cancer predisposition
genes and pathogenic missense variants in BRCA1, BRCA2, and
TP53. We assessed whether co-observation of pathogenic
variants in two different genes occurred more or less often
than expected under the assumption of independence.
Co-observation of pathogenic variants in each of BRCA1,
BRCA2, and PALB2 with the remaining genes was less frequent
than expected. This evidence for depletion remained after
adjustment for age at diagnosis, study design (familial
versus population-based), and country. Co-observation of a
variant of uncertain significance in BRCA1, BRCA2, or PALB2
with a pathogenic variant in another breast cancer gene
equated to supporting evidence against pathogenicity
following criterion strength assignment based on the
likelihood ratio and showed utility in reclassification of
missense BRCA1 and BRCA2 variants identified in BRIDGES. Our
approach has applicability for assessing the value of
co-observation as a predictor of variant pathogenicity in
other clinical contexts, including for gene-specific
guidelines developed by ClinGen Variant Curation Expert
Panels.},
keywords = {ACMG/AMP (Other) / BP5 (Other) / breast cancer (Other) /
co-observation (Other) / genetics (Other) / sequencing data
(Other) / variant classification (Other)},
cin = {C020 / B072},
ddc = {570},
cid = {I:(DE-He78)C020-20160331 / I:(DE-He78)B072-20160331},
pnm = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
pid = {G:(DE-HGF)POF4-313},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39096911},
doi = {10.1016/j.ajhg.2024.07.004},
url = {https://inrepo02.dkfz.de/record/292080},
}