Hereditary Cancer Genetics Practice Cases

In a hereditary cancer vignette, connect the personal and family history with the testing question. Identifying a familiar cancer-gene association is useful, but the case may instead ask who to test or how to interpret a negative result.

Build the family context

Note the cancer types, ages at diagnosis, relationships, and which side of the family is involved. Identify whether a familial pathogenic variant has already been established. A family-history pattern and a confirmed molecular result provide different kinds of information.

When possible, testing a person with a relevant cancer can be more informative than beginning with an unaffected relative. The best available person and the appropriate test still depend on the full history and clinical context.

Practice case: A negative panel in an unexplained family

An unaffected 36-year-old woman has a negative hereditary cancer panel. Her mother had breast cancer at 39 and her maternal aunt had ovarian cancer at 47. Both affected relatives are living and have not had genetic testing. No familial pathogenic variant is known. Which interpretation and next step are most appropriate?

1. Treat the result as a true negative and base screening on population risk.
2. Attribute the family history to polygenic risk and close the hereditary assessment.
3. Use personal and family history to guide care and consider testing an affected relative.
4. Treat the family as having confirmed BRCA1-related disease and use variant-specific family testing.

Answer: C. This result may be an uninformative negative. Without an established familial variant, it does not resolve the family history. Testing an affected relative may be more informative. A overinterprets the negative result; B assigns an unproven explanation; D assumes a specific molecular diagnosis that has not been established.

NCI genetic testing fact sheet

Compare with a known familial variant

If a laboratory specifically evaluates a known familial pathogenic variant and does not find it, that negative result has a different interpretation from a negative panel in an unexplained family. It does not mean the person has no cancer risk from any cause. Keep the tested question and the broader clinical picture separate.

Practice interpretation rather than isolated gene lists

Compare pathogenic or likely pathogenic findings, variants of uncertain significance, and negative results in their family context. For an uncertain finding, review the glossary's explanation of a variant of uncertain significance. For questions about what an assay evaluated, use the genetic test selection guide.

Use EveryGene Academy for case practice and the free Pedigree Workbook for family-history reasoning. Explore the 101 Must-Know Genetic Conditions flashcards for condition-focused review.

Sources: NCI BRCA testing fact sheet; BRCA1 and BRCA2 GeneReviews.

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