Limitations of direct-to-consumer (DTC) genetic testing for hereditary breast and ovarian cancer.

Abstract

10515 Background: With the advent of DTC genetic testing, individuals have access to genetic testing without input from a healthcare professional. DTC testing now exists for the 3 Ashkenazi Jewish (AJ) BRCA1/2 founder variants. DTC testing may provide false reassurance to individuals that they do not carry a pathogenic or likely pathogenic variant (PLPV) in BRCA1/2 or other cancer-risk genes. Methods: Multi-panel genetic testing was performed in 348,692 individuals for a clinical indication of hereditary breast/ovarian cancer (Clinical cohort) and 7,636 self-referred ostensibly healthy individuals (Healthy cohort) by a clinical testing laboratory. The primary analysis evaluated PLPVs for Group 1 genes: BRCA1/2 AJ founder variants and Group 2: full sequence BRCA1/2. Secondary analyses assessed PLPVs in Group 3: high-risk breast cancer genes ( BRCA1/2, CDH1, PALB2, PTEN, STK11, TP53), Group 4: all breast or ovarian cancer-risk genes (Group 3 genes plus ATM, BARD1, BRIP1, truncating CHEK2, EPCAM, MLH1, MSH2/6, NF1, PMS2, RAD51C/D) and Group 5: 41 cancer-risk genes; these analyses were limited to participants who tested for all 41 genes. Potentially mosaic variants were excluded. Results: Table illustrates PLPVs found in both cohorts. The BRCA1/2 AJ founder variants account for only ̃11% (1513/13,987) and ̃30% (19/64) of the BRCA PLPVs in the Clinical and Healthy cohorts, respectively. Even among AJ individuals, testing only for the 3 founder variants will miss ̃10% (52/513) of all BRCA1/2 PLPVs. Evaluating only the BRCA AJ founder variants missed a higher percentage of PLPVs in other cancer-risk genes. Conclusions: The 3 BRCA1/2 AJ founder variants analyzed by DTC testing account for a small fraction of PLPVs in cancer-risk genes in the general population, and miss 10% of BRCA PLPVs even among AJ individuals. Greater public education is needed to dispel the misconception that DTC tests are equivalent to clinical assessment and comprehensive genetic testing. PLPVs identified in Clinical and Healthy Cohorts.[Table: see text]