In which individuals should cancer‑predisposition gene testing be offered and what is the recommended testing strategy?

Cancer Predisposition Gene Testing: Who Should Be Tested and How

All individuals with epithelial ovarian, fallopian tube, or primary peritoneal cancer should be offered genetic testing regardless of age or family history, and testing should include at minimum BRCA1/2 with consideration for broader panel testing. 1

High-Priority Testing Indications (Test Immediately)

Ovarian/Fallopian Tube/Peritoneal Cancer

• Every woman with high-grade non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer warrants genetic testing at any age, even without family history 1, 2
• 13-18% of women with ovarian cancer carry BRCA1/2 mutations 1
• Testing should not delay primary treatment but should be initiated at diagnosis 1

Breast Cancer

• Age ≤50 years: Offer testing to all patients regardless of other factors 1
• Triple-negative breast cancer ≤60 years: Strong association with BRCA1 mutations (test all patients) 1
• Male breast cancer: 15-20% carry BRCA1/2 mutations (test at any age) 1
• Two or more primary breast cancers in the same individual 1
• Age >65 years: Offer testing selectively when triple-negative disease, family history suggestive of hereditary predisposition, Ashkenazi Jewish ancestry, or PARP-inhibitor eligibility exists 3

Pancreatic Cancer

• Ashkenazi Jewish ancestry with pancreatic cancer at any age (5.5-31% carry founder mutations) 1
• Pancreatic cancer plus a close relative with pancreatic cancer (2.8-17% have BRCA2 mutations) 1
• Three or more cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer in family 1
• Three or more cases of pancreatic cancer and/or melanoma 1

Prostate Cancer

• Three or more first-degree relatives with prostate cancer 1
• Two or more cases diagnosed before age 55 1
• Aggressive prostate cancer (Gleason ≥7) plus two or more cases of breast, ovarian, or pancreatic cancer 1

Colorectal Cancer

• Age <30 years with deficient mismatch repair (dMMR) CRC: Perform Lynch syndrome constitutional panel test first, followed by tumor somatic testing if negative 1
• Age <30 years with proficient mismatch repair (pMMR) CRC: Perform constitutional CRC multiple gene panel test 1
• In very young patients (≤35 years), 35% have identifiable hereditary syndromes, with Lynch syndrome (23.3%) and FAP (8.3%) most common 1

Gastric Cancer

• Diffuse gastric cancer diagnosed before age 40 1
• Lobular breast cancer AND diffuse gastric cancer in the same person 1
• Lobular breast cancer in one relative and diffuse gastric cancer in another, one diagnosed before age 50 1
• Two cases of gastric cancer in family, one confirmed diffuse gastric cancer diagnosed before age 50 1
• Three or more relatives with gastric cancer 1

Other High-Risk Scenarios

• Pheochromocytoma or paraganglioma: Approximately 30-40% are hereditary; SDHB mutations carry particularly high risk of malignancy and death 4
• First-degree relative with any of the above cancers meeting criteria 1, 2

Recommended Testing Strategy

Step 1: Test the Affected Individual First

• Always test the person with cancer when possible, as they have the highest likelihood of carrying a mutation 2
• If the affected relative tests positive, unaffected family members can undergo targeted single-mutation testing (faster and less expensive) 2
• Testing can be performed on deceased affected relatives using archived tissue if no living affected relative is available 3

Step 2: Choose Appropriate Test Type

Single-Gene vs. Multi-Gene Panel:

• For classic BRCA-associated cancers (ovarian, breast in young women, male breast), BRCA1/2 testing is minimum requirement 1
• Multi-gene panels detect additional mutations in 5.6% of patients beyond Lynch syndrome genes in suspected Lynch syndrome populations 5
• In one study of 1,260 suspected Lynch syndrome patients, panel testing identified 15 with BRCA1/2 mutations, 5 with APC mutations, 3 with biallelic MUTYH mutations, and 1 with STK11 mutation—all unexpected based on history 5
• Panels are particularly valuable when phenotype is atypical or family history is limited 5, 6

Genes to Include Based on Presentation:

• Breast/ovarian cancer panels: BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53 (if age <30), PTEN, CDH1 1, 3
• Pancreatic cancer panels: BRCA2, PALB2, ATM, CDKN2A, STK11 1, 7
• Colorectal cancer panels: MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, PTEN, STK11, SMAD4, BMPR1A 1, 5
• Gastric cancer: CDH1 (25-50% of hereditary diffuse gastric cancer) 1
• Pheochromocytoma: SDHB, SDHD, SDHC, SDHA, SDHAF2, VHL, RET, NF1, TMEM127, MAX 4

Step 3: Age-Specific Considerations

• Age <30 years with tumor-identified pathogenic variant: Test for TP53, APC, RB1, PTEN, CDKN2A, SMARCA4 3
• Age >45 years: Exercise caution with TP53 testing due to clonal hematopoiesis of indeterminate potential (CHIP) potentially causing false-positive results 3, 8
• Age >65 years: Testing remains valuable for therapeutic decisions (PARP inhibitors) and family cascade testing, but consider comorbidities and patient preferences 3, 8

Pre-Test Counseling Requirements

Mandatory Discussion Points:

• Probability of finding a mutation based on personal and family history 1, 2
• Implications for the patient: enhanced surveillance, risk-reducing surgeries, therapeutic options 1, 2
• Implications for family members: cascade testing recommendations 1, 2
• Meaning of possible results: pathogenic variant, variant of uncertain significance (VUS), or negative result 1
• VUS occur in 38% of multi-gene panel tests and should not influence clinical management 5
• Testing must be voluntary with informed consent 1

Special Population Considerations

Ashkenazi Jewish Ancestry

• Founder mutations increase BRCA1 prevalence to 1 in 40 and BRCA2 to 1 in 40 (vs. 1 in 300 and 1 in 800 in general population) 1
• Test for breast or pancreatic cancer at any age 1

Lynch-Like Syndrome (dMMR Tumor Without Germline Mutation)

• If tumor shows deficient mismatch repair but no germline mutation identified, perform somatic tumor testing with CRC gene panel 1
• If double somatic mutations identified: manage based on family history of colorectal cancer 1
• If no or single somatic mutation identified: manage as Lynch syndrome with appropriate surveillance 1

Unaffected Individuals with Family History

• When first-degree relative carries known Lynch syndrome mutation, offer testing for that specific mutation at age ≥18 years 3
• Without known family mutation but suggestive history, use validated risk-prediction models (PREMM 1,2,6 or MMRpro); predicted probability >5% warrants germline testing 3

Critical Pitfalls to Avoid

Testing Pitfalls

• Do not delay cancer treatment for genetic counseling referral 1
• Do not use VUS results to guide clinical management; follow patients for possible reclassification 3
• Do not screen for ovarian cancer even in high-risk women—screening does not reduce mortality and causes harm through false-positives (20:1 ratio of surgeries to screen-detected cancers) 2
• Do not interpret TP53 mutations in patients >45 years without considering CHIP as alternative explanation 3, 8

Genetic Counseling Pitfalls

• Maternal imprinting: SDHD and SDHAF2 mutations only cause disease when inherited from father, potentially creating falsely negative family histories 1, 4
• Incomplete family history: Small family size or early deaths from non-cancer causes can mask hereditary patterns 9
• Multiple primary cancers: Even without family history, multiple primary cancers in one individual warrant testing 9

Management Pitfalls

• Risk-reducing surgery, not screening, is the evidence-based approach for BRCA carriers 2
• Risk-reducing salpingo-oophorectomy timing: ages 35-40 for BRCA1, ages 40-45 for BRCA2 (after childbearing complete) 2
• Enhanced breast surveillance with MRI and mammography should begin at age 25-30 for BRCA carriers 2

Testing Facility Requirements

• Use CLIA-approved laboratories with internal and external quality control systems 1
• Testing should include at minimum BRCA1/2 and consider MSI or DNA mismatch repair if not previously done 1
• Homologous recombination deficiency (HRD) evaluation may inform maintenance therapy decisions 1