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. 2024 Sep 5;111(9):2059-2069.
doi: 10.1016/j.ajhg.2024.07.004. Epub 2024 Aug 2.

Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

Aimee L Davidson  1 , Kyriaki Michailidou  2 , Michael T Parsons  1 , Cristina Fortuno  1 , Manjeet K Bolla  3 , Qin Wang  3 , Joe Dennis  3 , Marc Naven  3 , Mustapha Abubakar  4 , Thomas U Ahearn  4 , M Rosario Alonso  5 , Irene L Andrulis  6 , Antonis C Antoniou  3 , Päivi Auvinen  7 , Sabine Behrens  8 , Marina A Bermisheva  9 , Natalia V Bogdanova  10 , Stig E Bojesen  11 , Thomas Brüning  12 , Helen J Byers  13 , Nicola J Camp  14 , Archie Campbell  15 , Jose E Castelao  16 , Melissa H Cessna  17 , Jenny Chang-Claude  18 , Stephen J Chanock  4 , Georgia Chenevix-Trench  19 ; NBCS Collaborators; J Margriet Collée  20 , Kamila Czene  21 , Thilo Dörk  22 , Mikael Eriksson  21 , D Gareth Evans  23 , Peter A Fasching  24 , Jonine D Figueroa  25 , Henrik Flyger  26 , Manuela Gago-Dominguez  27 , Montserrat García-Closas  28 , Gord Glendon  29 , Anna González-Neira  5 , Felix Grassmann  30 , Jacek Gronwald  31 , Pascal Guénel  32 , Andreas Hadjisavvas  33 , Lothar Haeberle  24 , Per Hall  34 , Ute Hamann  35 , Mikael Hartman  36 , Peh Joo Ho  37 , Maartje J Hooning  38 , Reiner Hoppe  39 , Anthony Howell  40 ; kConFab Investigators; Anna Jakubowska  41 , Elza K Khusnutdinova  42 , Vessela N Kristensen  43 , Jingmei Li  44 , Joanna Lim  45 , Annika Lindblom  46 , Jenny Liu  47 , Artitaya Lophatananon  48 , Arto Mannermaa  49 , Dimitrios A Mavroudis  50 , Arjen R Mensenkamp  51 , Roger L Milne  52 , Kenneth R Muir  48 , William G Newman  23 , Nadia Obi  53 , Mihalis I Panayiotidis  33 , Sue K Park  54 , Tjoung-Won Park-Simon  22 , Paolo Peterlongo  55 , Paolo Radice  56 , Muhammad U Rashid  57 , Valerie Rhenius  3 , Emmanouil Saloustros  58 , Elinor J Sawyer  59 , Marjanka K Schmidt  60 , Petra Seibold  8 , Mitul Shah  61 , Melissa C Southey  62 , Soo Hwang Teo  63 , Ian Tomlinson  64 , Diana Torres  65 , Thérèse Truong  32 , Irma van de Beek  66 , Annemieke H van der Hout  67 , Camilla C Wendt  68 , Alison M Dunning  61 , Paul D P Pharoah  69 , Peter Devilee  70 , Douglas F Easton  71 , Paul A James  72 , Amanda B Spurdle  73
Collaborators, Affiliations

Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset

Aimee L Davidson et al. Am J Hum Genet. .

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; BP5; breast cancer; co-observation; genetics; sequencing data; variant classification.

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Conflict of interest statement

Declaration of interests P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessments and variant interpretation of VUSs in BRCA1 and BRCA2. The funds were paid to the institution.

Figures

None
Graphical abstract
Figure 1
Figure 1
Observation of pathogenic variants (PVs) in hereditary breast cancer genes within the BRIDGES breast cancer-affected cohort The BRIDGES breast cancer affected cohort consists of 55,815 individuals. (A) Number of unique PVs observed in the cohort. (B) Number of PVs observed within the cohort with the proportion of individuals with at least one PV in the designated gene given above bars. (C) Number of PV co-observations, shown for each gene pair. PVs in CDH1 or PTEN were not co-observed with a PV in another gene. Final figure formatting performed using Inkscape (v.0.92.3).
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