How should clinicians approach a patient with a relative with ovarian cancer but negative BRCA testing?

Conclude no hereditary risk

Consider non-BRCA hereditary syndromes (e.g., Lynch, PALB2, RAD51C), broader panel testing, and a detailed family history

A negative BRCA test in a relative does not rule out hereditary risk for ovarian cancer. The best approach is to expand the assessment beyond BRCA and rely on a thorough family history to guide testing. Ovarian cancer can be part of other hereditary syndromes and is linked to multiple genes besides BRCA1/BRCA2, including Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2) and other ovarian cancer susceptibility genes such as PALB2, RAD51C, RAD51D, and BRIP1. A comprehensive multi-gene panel can uncover pathogenic variants that BRCA testing alone would miss.

Begin with a detailed three-generation family history to look for patterns of cancer that suggest heritable risk, then pursue genetic counseling and targeted testing of the patient using a broader panel if indicated. If a pathogenic variant is found, cascade testing of relatives follows and management can be tailored accordingly. Even without a positive result, the family history may still justify surveillance and risk-reduction strategies appropriate to the hereditary risk pattern.

Only test for BRCA1 and BRCA2 again

Attribute to environmental factors and stop testing

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