Enter Note Done


Keywords: Cancer; Genetic testing; Mutation detection; Cancer syndromes; Clinical testing

D.E. Pineda-Alvarez; S.T. Michalski; M. Russell; S. Yang; I.Y. Song; E.D. Esplin

Affiliation: Invitae, 1400 16th Street, San Francisco, CA, 94103


Germline and tumor genetic testing are both increasingly used in precision treatment of individuals with cancer. These tests are frequently ordered separately in clinical practice but have the potential to inform one another. Recent studies report that approximately 10% of patient’s tumors have clinically significant variants in genes known to predispose to hereditary cancer, however, it has been unclear which patients or findings deserve follow-up with germline testing (GT). Here, we retrospectively reviewed a cohort of individuals who had tumor testing followed by GT. We report the concordance rate between germline and tumor variants, and the impact on the patient’s medical management and implications for their relatives.


Our study used de-identified data from 1043 consecutive patients who underwent tumor genetic testing followed by GT with NGS-based hereditary cancer gene panels.


Tumor genetic testing results included variants in BRCA2 (290), BRCA1 (174), TP53 (158), ATM (70), MLH1 (65), APC (65), PMS2 (61), MSH6 (58), PTEN (54) and CDH1 (42). In 364/1043 cases (35%) the variant was detected as likely pathogenic or pathogenic (LP/P) in the germline. Genes in which variants were confirmed to be germline in >60% of patients included: FANCA, AXIN2, RAD50, MUTYH, BLM, PALB2, CHEK2, FANCD2, MITF, SDHB. Variants in FH, BRCA2, RET, ATM, SDHA, BRIP1, MSH2, BRCA1, BAP1, EGFR, and RAD51D were confirmed in the germline in <60% of patients. Variants were rarely detected as germline for TP53 (3%), APC (3%), PTEN (2%) and none were detected for CDKN2A, NF1 and STK11. In 24 (2%) cases a LP/P germline variant was detected but not reported in the tumor.


One-third of the patients with clinically significant variants in tumors were identified to carry the same variant in the germline, uncovering a previously unknown risk of hereditary cancer. Notably, some genes had a high probability of variants occurring in the germline, while others were primarily seen in tumors. Interestingly, 6% of the germline variants were not included in the tumor report due to technical and gene content differences in either assay or due to differences of clinical classification between tumor and germline testing. Performing simultaneous germline and tumor testing may inform susceptibility to a hereditary cancer disorder, identify targets for precision therapy, early detection of secondary malignancies, and guide genetic counseling for relatives.