Abstract P5-09-19: The complexity of germline panel testing: Cost, access and variant interpretation in an Irish context
Authors: O'Donovan EM , Farrell M , Gallagher D 
Published: May 2019

Abstract
Objectives
Diagnostic germline genetic testing of single or multiple cancer predisposition genes is increasingly central to the care of women with breast cancer. Testing for mutations in BRCA1/2 has therapeutic relevance in perioperative and metastatic settings. Variants of uncertain significance (VUS) are identified in approximately 5-20% of tests. Single gene testing in the Rep. of Ireland occurs through 3 clinics using laboratories in England. Panel testing is offered through Color Genomics and Myriad Genetics. Color genomics offers a less expansive panel test. Panels have made variant interpretation a common clinical challenge. We investigated interpretation of 10 VUS in 3 laboratories.
Methods
We selected 10 patients who had VUS reported in BRCA1/2 in NHS laboratories. Further diagnostic testing for mutations in BRCA1/2 was subsequently completed using BRACAnalysis on stored DNA from these individuals. Patients were re-contacted and offered Color panel testing for mutations in 30 genes. Previous test reports were not provided to either company. A review of all 10 BRCA1/2 VUS was performed on ClinVar database.
Results
Two VUS in BRCA1 and 8 VUS in BRCA2 were included in the study. Retesting was completed at a median time of 20mths (14-70mths) after the original testing. All 10 individuals underwent BRCAnalysis testing, only 7 had panel testing (2 did not make contact following calls/ letters, 1 had left Ireland). ClinVar classified 3 variants as benign, 2 likely benign, 2 VUS and 2 pathogenic (1not on ClinVar). All 10 VUS were re-classified by Myriad and Color. One result was deemed 'pathogenic' by Color and 'suspected deleterious' by Myriad (pt 9, table 1). Panel testing identified two additional VUS: an MSH6 and a RAD51.
Interpretation of testing CliniVarNHS laboratory testingMyriadColor GenomicsPtDatabase ReviewGeneexon BRACAnalysis30 gene panel test1Benign (2018)BRCA111c.3708T&gt;G, p.(Asn1236Lys)No deleterious mutationMSH6 VUS c.2585T&gt;A (p.Leu862Gln)2Benign (2015)BRCA111c.4910C&gt;T, p.(Pro1637Leu)No deleterious mutationNo mutations identified3Not on ClinVarBRCA211c.3037A&gt;G, p.(Lys1025Glu)No deleterious mutationNo mutations identified4Pathogenic (2016)BRCA23c.316+5G&gt;CDeleterious MutationNo sample submitted5VUS (2016)BRCA24c.343A&gt;G , p.(Lys115Glu)No deleterious mutationNo mutations identified6Likely benign (2016)BRCA211c.5635G&gt;A, p.(Glu1879Lys)No deleterious mutationRAD51D VUS c.26G&gt;C (p.Cys9Ser)7Benign (2017)BRCA211c.6821G&gt;T, p.(Gly2274Val)No deleterious mutationNo sample submitted8Likely Benign (2018)BRCA215c.7601C&gt;T, p.(Ala2534Val)No deleterious mutationvNo mutations identified9Pathogenic (2017)BRCA217c.7958T&gt;C, p.(Leu2653Pro)Suspected deleterious mutationBRCA2, c.7958T&gt;C, p.(Leu2653Pro) PATHOGENIC10VUS (2016)BRCA219c.8351G&gt;A, p.(Arg2784Gln)No deleterious mutationNo sample submitted
Conclusions
All 10 VUS in BRCA1/2 were reclassified with additional testing by two commercial laboratories at a later date. The results of this testing by two different companies are clinically concordant. Panel testing identified 2 additional VUS in potentially clinically relevant genes. Less expansive testing increases access to germline genetic testing but requires responsible interpretation.
Citation Format: O'Donovan EM, Farrell M, Gallagher D. The complexity of germline panel testing: Cost, access and variant interpretation in an Irish context [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-19.