Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

TY - JOUR

T1 - Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

AU - Zanti, Maria

AU - O'Mahony, Denise G

AU - Parsons, Michael T

AU - Dorling, Leila

AU - Dennis, Joe

AU - Boddicker, Nicholas J

AU - Chen, Wenan

AU - Hu, Chunling

AU - Naven, Marc

AU - Yiangou, Kristia

AU - Ahearn, Thomas U

AU - Ambrosone, Christine B

AU - Andrulis, Irene L

AU - Antoniou, Antonis C

AU - Auer, Paul L

AU - Baynes, Caroline

AU - Bodelon, Clara

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Brantley, Kristen D

AU - Camp, Nicola J

AU - Campbell, Archie

AU - Castelao, Jose E

AU - Cessna, Melissa H

AU - Chang-Claude, Jenny

AU - Chen, Fei

AU - Chenevix-Trench, Georgia

AU - Conroy, Don M

AU - Czene, Kamila

AU - De Nicolo, Arcangela

AU - Domchek, Susan M

AU - Dörk, Thilo

AU - Dunning, Alison M

AU - Eliassen, A Heather

AU - Evans, D Gareth

AU - Fasching, Peter A

AU - Figueroa, Jonine D

AU - Flyger, Henrik

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - Glendon, Gord

AU - González-Neira, Anna

AU - Grassmann, Felix

AU - Hadjisavvas, Andreas

AU - Haiman, Christopher A

AU - Hamann, Ute

AU - Hart, Steven N

AU - Hartman, Mikael B A

AU - Ho, Weang-Kee

AU - Hodge, James M

AU - Hoppe, Reiner

AU - Howell, Sacha J

AU - Jakubowska, Anna

AU - Khusnutdinova, Elza K

AU - Ko, Yon-Dschun

AU - Kraft, Peter

AU - Kristensen, Vessela N

AU - Lacey, James V

AU - Li, Jingmei

AU - Lim, Geok Hoon

AU - Lindström, Sara

AU - Lophatananon, Artitaya

AU - Luccarini, Craig

AU - Mannermaa, Arto

AU - Martinez, Maria Elena

AU - Mavroudis, Dimitrios

AU - Milne, Roger L

AU - Muir, Kenneth

AU - Nathanson, Katherine L

AU - Nuñez-Torres, Rocio

AU - Obi, Nadia

AU - Olson, Janet E

AU - Palmer, Julie R

AU - Panayiotidis, Mihalis I

AU - Patel, Alpa V

AU - Pharoah, Paul D P

AU - Polley, Eric C

AU - Rashid, Muhammad U

AU - Ruddy, Kathryn J

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J

AU - Schmidt, Marjanka K

AU - Southey, Melissa C

AU - Tan, Veronique Kiak-Mien

AU - Teo, Soo Hwang

AU - Teras, Lauren R

AU - Torres, Diana

AU - Trentham-Dietz, Amy

AU - Truong, Thérèse

AU - Vachon, Celine M

AU - Wang, Qin

AU - Weitzel, Jeffrey N

AU - Yadav, Siddhartha

AU - Yao, Song

AU - Zirpoli, Gary R

AU - Cline, Melissa S

AU - Devilee, Peter

AU - Tavtigian, Sean V

AU - Goldgar, David E

AU - Couch, Fergus J

AU - Easton, Douglas F

AU - Spurdle, Amanda B

AU - Michailidou, Kyriaki

AU - NBCS Collaborators

PY - 2024/9/4

Y1 - 2024/9/4

N2 - Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

AB - Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

U2 - 10.1101/2024.09.04.24313051

DO - 10.1101/2024.09.04.24313051

M3 - SCORING: Journal article

C2 - 39281752

JO - medRxiv

JF - medRxiv

ER -