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

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.