{Reference Type}: Journal Article
{Title}: Co-observation of germline pathogenic variants in breast cancer predisposition genes: Results from analysis of the BRIDGES sequencing dataset.
{Author}: Davidson AL;Michailidou K;Parsons MT;Fortuno C;Bolla MK;Wang Q;Dennis J;Naven M;Abubakar M;Ahearn TU;Alonso MR;Andrulis IL;Antoniou AC;Auvinen P;Behrens S;Bermisheva MA;Bogdanova NV;Bojesen SE;Brüning T;Byers HJ;Camp NJ;Campbell A;Castelao JE;Cessna MH;Chang-Claude J;Chanock SJ;Chenevix-Trench G; ;Collée JM;Czene K;Dörk T;Eriksson M;Evans DG;Fasching PA;Figueroa JD;Flyger H;Gago-Dominguez M;García-Closas M;Glendon G;González-Neira A;Grassmann F;Gronwald J;Guénel P;Hadjisavvas A;Haeberle L;Hall P;Hamann U;Hartman M;Ho PJ;Hooning MJ;Hoppe R;Howell A; ;Jakubowska A;Khusnutdinova EK;Kristensen VN;Li J;Lim J;Lindblom A;Liu J;Lophatananon A;Mannermaa A;Mavroudis DA;Mensenkamp AR;Milne RL;Muir KR;Newman WG;Obi N;Panayiotidis MI;Park SK;Park-Simon TW;Peterlongo P;Radice P;Rashid MU;Rhenius V;Saloustros E;Sawyer EJ;Schmidt MK;Seibold P;Shah M;Southey MC;Teo SH;Tomlinson I;Torres D;Truong T;van de Beek I;van der Hout AH;Wendt CC;Dunning AM;Pharoah PDP;Devilee P;Easton DF;James PA;Spurdle AB;
{Journal}: Am J Hum Genet
{Volume}: 111
{Issue}: 9
{Year}: 2024 Sep 5
{Factor}: 11.043
{DOI}: 10.1016/j.ajhg.2024.07.004
{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.