What is the management approach for an individual with Endoglin (ENG) and SMAD4 variants of uncertain significance (VUS) mutations?

Management of Individuals with ENG and SMAD4 Variants of Uncertain Significance

When both ENG and SMAD4 variants are classified as VUS (variants of uncertain significance), you cannot use these genetic findings to guide clinical management—instead, apply the Curaçao clinical diagnostic criteria and manage based on clinical phenotype alone, while periodically reassessing variant classification as new evidence emerges. 1

Understanding VUS Classification

Variants of uncertain significance represent DNA changes where the association with clinical disease is unknown and cannot be used to inform clinical decisions at the time of testing 1. The critical distinction is:

• VUS ≠ Pathogenic mutation: A VUS does not confirm genetic disease and should not trigger mutation-specific screening protocols 1
• VUS classification changes over time: Periodic review is essential as new evidence accumulates from additional families, functional studies, and population databases 1

Immediate Clinical Approach

Apply Clinical Diagnostic Criteria

Use the Curaçao criteria to establish HHT diagnosis clinically, requiring 3 of 4 features: spontaneous/recurrent epistaxis, multiple telangiectasias at characteristic sites, visceral arteriovenous malformations, or affected first-degree relative with HHT 2, 3. The diagnosis is:

• Definite: 3 or more criteria present
• Possible/suspected: 2 criteria present
• Unlikely: Fewer than 2 criteria 2

Risk Stratification Based on Clinical Phenotype

If the patient meets clinical criteria for definite HHT (3+ Curaçao criteria), proceed with standard HHT screening regardless of VUS status 2:

• Screen for pulmonary AVMs using contrast echocardiography or chest CT 2, 3
• Perform brain MRI to detect cerebral vascular malformations 2, 3
• Conduct Doppler ultrasonography for hepatic involvement (never perform liver biopsy due to hemorrhage risk) 2, 3

If the patient has gastrointestinal polyps or family history of juvenile polyposis, initiate GI surveillance even with SMAD4 VUS 1:

• Begin colonoscopic surveillance at age 15 years or earlier if symptomatic, with 1-3 year intervals based on polyp burden 1
• Consider upper GI endoscopy if gastric symptoms present 1

Strategies to Reclassify VUS

Pursue Variant Reclassification Through Multiple Approaches

Collect family segregation data by testing affected and unaffected relatives—two unrelated families with the same rare variant and disease phenotype provide strong evidence for pathogenicity 1. This approach successfully reclassified a BRCA1 VUS from class 3 (uncertain) to class 5 (definitely pathogenic) through international collaboration 1.

Submit clinical and genetic data to variant registries including the ENIGMA consortium or disease-specific databases, which facilitate linking clinical teams managing families with identical VUS to pool evidence 1. For SMAD4 specifically, testing affected relatives over age 60 years helps estimate penetrance and cancer risk 1.

Request functional testing when available—assays showing partial loss of normal transcript from aberrant splicing or reduced protein function may provide additional evidence for classification 1. In silico prediction tools (PolyPhen2, SIFT) can assess whether amino acid substitutions affect protein structure and function 1.

Testing Strategy for Related Family Members

Test the most clearly affected family member first rather than the asymptomatic individual with VUS 1. If an affected relative tests positive for a pathogenic variant in ENG or SMAD4, this confirms the familial genetic disease and allows interpretation of the VUS in context 1.

Avoid direct testing of additional asymptomatic relatives until variant pathogenicity is established, as this creates difficulty determining relevance of identified variants in healthy individuals and increases risk of false-positives 1.

Management During VUS Uncertainty Period

Conservative Clinical Surveillance Approach

Implement symptom-based monitoring rather than mutation-specific protocols 1:

• Monitor for epistaxis frequency, duration, and severity
• Assess for new telangiectasias on lips, oral cavity, fingers, and nose
• Screen for anemia with complete blood count if bleeding symptoms present
• Evaluate for gastrointestinal bleeding or polyps if abdominal symptoms develop

Do NOT perform aggressive screening for asymptomatic AVMs based solely on VUS findings, as the penetrance and cancer risk remain uncertain when variants are unclassified 1.

Specific Pitfalls to Avoid

Never perform risk-reducing surgery (such as prophylactic colectomy or organ-specific interventions) based on VUS alone, as the penetrance for these variants remains uncertain 1. Risk-reducing procedures should only be considered with extreme caution where there is clear personal or family history of disease 1.

Do not provide false reassurance if genetic testing shows only VUS—negative or uncertain genetic testing cannot reliably exclude disease in related family members, particularly since 7% of patients with known disease may have negative genetic testing despite clinical manifestations 1.

Avoid population-based screening panels in asymptomatic individuals without confirmed familial disease, as this increases likelihood of VUS and false-positives, especially in underrepresented populations where variant allele frequencies may be unknown 1.

Genetic Counseling Considerations

Provide pretest and posttest genetic counseling emphasizing that VUS results do not confirm or exclude genetic disease 1. Explain that:

• VUS classification may change over time as new evidence emerges 1
• Clinical phenotype, not genetic testing, should guide immediate management decisions 1
• Additional family testing may help clarify variant significance 1

Discuss autosomal dominant inheritance if either variant is later reclassified as pathogenic—each child would have 50% risk of inheriting the mutation 2, 4.

When to Escalate Management

Reclassify management approach if the VUS is upgraded to likely pathogenic or pathogenic 1:

If ENG VUS → Pathogenic

• Implement HHT1-specific screening with emphasis on pulmonary and cerebral AVMs (more frequent and larger in HHT1) 3
• Screen for transcutaneous oxygen saturation abnormalities 3
• Initiate stepwise bleeding management: nasal moisturization → oral tranexamic acid → local ablative therapies → systemic bevacizumab for refractory cases 3

If SMAD4 VUS → Pathogenic

• Recognize combined juvenile polyposis-HHT overlap syndrome risk (occurs in 1-2% of HHT cases, with up to 76% manifesting HHT features) 4, 3
• Initiate upper GI tract surveillance every 1-3 years starting at age 18 years due to 73% prevalence of gastric polyposis and exclusive occurrence of gastric cancers in SMAD4 carriers 4, 3
• Begin colonoscopy with polypectomy at 2-year intervals for colorectal surveillance (cumulative lifetime CRC risk 39-68%) 4
• Screen for all HHT-related AVMs (pulmonary, cerebral, hepatic) as SMAD4 patients remain at risk even without overt HHT symptoms 4
• Coordinate care through specialized HHT center with experience managing both HHT and juvenile polyposis complications 4, 3

Request periodic variant reclassification from the testing laboratory, typically annually or when new family members are tested, as classifications are likely to change over time with accumulating evidence 1.