What are the implications of a pathogenic PMS2 gene variant for my breast cancer patient's cancer risk and management?

Implications of a Pathogenic PMS2 Gene Variant in Breast Cancer

A pathogenic PMS2 gene variant (c.1939A>T) in your breast cancer patient indicates Lynch syndrome, which primarily increases her risk for colorectal and endometrial cancers, with a smaller increased risk for breast cancer compared to other Lynch syndrome genes.

Understanding PMS2 and Lynch Syndrome

PMS2 is one of the DNA mismatch repair (MMR) genes associated with Lynch syndrome. When pathogenic variants occur in this gene, they cause deficiencies in DNA repair mechanisms, leading to increased cancer risks.

Cancer Risk Profile for PMS2 Carriers:

• Colorectal cancer: 12-13% lifetime risk (compared to 4.7-6.6% in general population) 1
• Endometrial cancer: 13% lifetime risk (compared to 2.4% in general population) 1, 2
• Breast cancer: Some evidence suggests increased risk, particularly with PMS2 mutations 3, 4
• Other Lynch-associated cancers: Limited evidence for increased risk of ovarian, gastric, small bowel, and other cancers 2

Recommended Management

Colorectal Cancer Surveillance:

• Begin colonoscopy: At age 45 or 10 years before earliest colorectal cancer diagnosis in the family, whichever comes first 1
• Frequency: Every 5 years 1

Gynecological Cancer Surveillance:

• Endometrial cancer screening: Consider annual endometrial sampling starting at age 30-35 1
• Risk-reducing surgery: Consider hysterectomy after childbearing is complete 1
• Note: Risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 carriers requires further discussion due to lower penetrance compared to other Lynch genes 2

Breast Cancer Management:

• Breast surveillance: Follow standard breast cancer screening guidelines based on personal and family history
• Note: While some studies show increased breast cancer risk with PMS2 variants 4, the evidence is not as strong as for other hereditary breast cancer genes

Other Cancer Surveillance:

• Gastric and small bowel: Routine surveillance not recommended for PMS2 carriers unless in context of clinical trials 1
• H. pylori screening: Recommended with eradication therapy if positive 1

Family Implications

• Cascade testing: Recommend genetic testing for first-degree relatives (siblings, children) 1
• Inheritance pattern: Autosomal dominant (50% chance of passing to each child)
• Family counseling: Explain the moderate cancer risks associated with PMS2 variants compared to other Lynch syndrome genes

Important Considerations

• PMS2 penetrance: Lower cancer risks compared to MLH1 and MSH2 mutations 1, 2
• Age-specific risks: The average age of cancer presentation varies by gene and cancer type
• Pseudogene considerations: PMS2 has multiple pseudogenes that can complicate genetic testing interpretation; confirm the variant is not in a pseudogene 5
• Immunotherapy implications: If the patient develops metastatic disease, tumors with MMR deficiency may respond well to immunotherapy 6

Follow-up Recommendations

• Annual follow-up: Review surveillance adherence and update family history
• Multidisciplinary approach: Coordinate care between oncology, gastroenterology, and gynecology
• Research participation: Consider referral to clinical trials focused on Lynch syndrome management

This pathogenic PMS2 variant requires comprehensive cancer risk management, with particular attention to colorectal and endometrial cancer surveillance, while maintaining appropriate breast cancer follow-up based on her personal history.