What genetic testing is appropriate for an Ashkenazi Jewish patient with a grandparent and first‑cousin with pancreatic cancer?

Genetic Testing for Ashkenazi Jewish Patient with Family History of Pancreatic Cancer

This patient should undergo genetic counseling and testing for BRCA1/2 mutations, with strong consideration for expanded panel testing including PALB2, ATM, CDKN2A, and Lynch syndrome genes. 1

Primary Recommendation: BRCA Testing

Ashkenazi Jewish ancestry alone with any family history of pancreatic cancer is an indication for genetic testing, regardless of the degree of relationship. 1 The American College of Medical Genetics and Genomics explicitly states that referral should be considered for "Ashkenazi Jewish ancestry and pancreatic cancer at any age" in the patient or first-degree relatives. 1

Key Evidence Supporting Testing:

• Ashkenazi Jewish individuals with pancreatic cancer have a 5.5-31% prevalence of BRCA1/2 mutations, with BRCA2 being more common than BRCA1. 1
• The three Ashkenazi Jewish founder mutations (BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT) are present in 1% of the Ashkenazi Jewish population. 1
• BRCA2 accounts for the highest percentage of known inherited pancreatic cancer causes, identified in 5-17% of familial pancreatic cancer kindreds. 1

Expanded Panel Testing Rationale

Beyond BRCA1/2, this patient warrants multi-gene panel testing because:

• PALB2 mutations occur in 0.9-3.7% of pancreatic cancer patients with familial history. 1
• ATM mutations are found in 2.4% of familial pancreatic cancer patients. 1
• CDKN2A (p16) mutations occur in 1.5-2.5% of moderate-to-high-risk families and confer a 13-22-fold increased risk. 1
• Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2) carry an 8.6-fold increased risk and 3.7% lifetime risk of pancreatic cancer. 1

Clinical Implications of Testing

If Mutation Identified:

Pancreatic cancer screening becomes indicated for this patient even without a first-degree relative affected, depending on the specific gene:

• BRCA2 carriers: Screening recommended with ≥1 first- or second-degree relative with pancreatic cancer, starting at age 50 or 10 years younger than earliest family diagnosis. 1
• CDKN2A carriers: Screening at age 40 or 10 years younger than earliest family diagnosis, no additional family history required. 1
• PALB2 carriers: Similar approach to BRCA2 carriers with family history. 1

Screening Modalities:

When indicated, screening should utilize contrast-enhanced MRI/MRCP and/or endoscopic ultrasound. 1

Important Caveats

The grandparent and first cousin relationship does not meet strict criteria for "familial pancreatic cancer" screening (which typically requires ≥2 first-degree relatives or ≥3 blood relatives with ≥1 first-degree). 1 However, the combination of Ashkenazi Jewish ancestry plus any family history of pancreatic cancer is sufficient indication for genetic testing. 1

Approximately 80% of familial pancreatic cancer cases have no identified genetic cause, but testing remains critical because identified mutations can guide treatment decisions (particularly for BRCA-related cancers and PARP inhibitor therapy) and inform family members. 2, 3

Practical Implementation

Refer to genetic counseling to:

• Document complete three-generation pedigree including breast, ovarian, melanoma, and colorectal cancers. 2, 3
• Discuss testing options and implications for family members. 1
• Coordinate cascade testing if mutation identified. 1

Testing should ideally be performed on affected family members first (the grandparent or cousin if available), but given high mortality of pancreatic cancer, testing this unaffected patient is appropriate. 1