Research Article| Volume 268, P22-27, November 2022

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Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing

Published:September 05, 2022DOI:


      • Recent guideline changes dramatically increase eligibility for germline testing among patients with somatic mutations in moderate risk breast and ovarian cancer susceptibility genes.
      • Traditional germline testing guidelines based on personal and family history do not adequately capture hereditary cancer syndromes associated with moderate risk breast and ovarian cancer genes among a cohort of advanced cancer patients.
      • Rates of germline confirmation are ∼40% or higher in patients with TGP-identified mutations in ATM, CHEK2, and PALB2.
      • In the context of limited healthcare resources, more study is needed to determine which TGP-identified mutations should be prioritized for referral to cancer genetics to maximize hereditary cancer syndrome diagnoses and limit the burden on cancer genetics clinics.



      Recent changes in oncology practice guidelines indicate that mutations in cancer susceptibility genes identified on tumor genomic profiling (TGP) should prompt confirmatory germline testing. Our study aimed to determine the proportion of patients with TGP-identified mutations in moderate risk breast and ovarian cancer genes who previously would not have been considered for germline testing.


      From January 2013 to September 2020, 7468 adult Stanford Health Care patients underwent TGP on solid tumor samples and 166 had TGP-identified mutations in moderate risk breast and ovarian cancer susceptibility genes (ATM, BRIP1, CHEK2, PALB2, RAD51C and RAD51D). Retrospective chart reviews were performed on 160 patients. Cases were analyzed to determine eligibility for germline testing using established NCCN criteria, and somatic and germline results were compared where both were available.


      Nearly half (45.3% [73/160]) of patients would not have been eligible for germline testing if not for a TGP-identified mutation in a moderate risk breast or ovarian cancer gene. Of the 64 cases that underwent germline testing, about half (51.5% [33/64]) had results that confirmed germline origin of the TGP finding. High rates of germline confirmation were found in PALB2 (100% [5/5]), ATM (40% [14/35]), CHEK2 (61.5% [8/13]), and BRIP1 (57.1% [4/7]).


      Our study shows that the presence of TGP-identified mutations in moderate risk breast and ovarian cancer genes increases eligibility for germline testing beyond those that would be eligible based largely on personal and family history criteria alone. Additionally, results of germline testing in these newly eligible cases supports that this expanded eligibility captures individuals with hereditary cancer syndromes that would not have otherwise been identified.


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