Is Promethease (Personalized Medicine Analysis) accurate enough to identify Lynch Syndrome risks within an uploaded genome?

Promethease is Not Accurate Enough for Lynch Syndrome Risk Assessment

Direct-to-consumer genomic analysis tools like Promethease are not recommended for identifying Lynch syndrome risk and should not replace clinical genetic testing with proper medical guidance. 1

Understanding Lynch Syndrome Diagnosis

Lynch syndrome is an autosomal dominant condition caused by pathogenic variants in DNA mismatch repair (MMR) genes - MLH1, MSH2, MSH6, and PMS2 - which significantly increases risk for colorectal, endometrial, and other cancers 2, 3.

Proper Diagnostic Approach

The American Gastroenterological Association (AGA) and National Comprehensive Cancer Network (NCCN) recommend a structured approach to Lynch syndrome identification:

1. Family History Assessment:

   • Collect detailed family history of cancers
   • Apply validated criteria (revised Bethesda or Amsterdam II criteria) 1

2. Risk Stratification:

   • Use validated prediction models like PREMM1,2,6 or MMRpro 1
   • These models are available online and provide probability estimates for carrying MMR gene mutations

3. Appropriate Testing:

   • For individuals with >5% probability of Lynch syndrome, proper germline genetic testing is recommended 1
   • For those with colorectal cancer, tumor testing with immunohistochemistry (IHC) or microsatellite instability (MSI) testing is strongly recommended 1

Why Promethease is Inadequate

Promethease and similar direct-to-consumer genomic analysis tools have significant limitations for Lynch syndrome detection:

• Inability to detect complex variants: Lynch syndrome can be caused by structural variants that require specialized detection methods like optical genome mapping and nanopore sequencing 4

• Limited interpretation capability: Accurate classification of variants requires cumulative information from patient outcomes and specialized experimental testing 2

• Lack of clinical validation: Guidelines specifically recommend validated clinical risk prediction models and proper genetic testing, not consumer genomic tools 1

• Missing comprehensive analysis: Lynch syndrome diagnosis often requires tumor tissue analysis with IHC or MSI testing, which consumer genomics cannot provide 1

Clinical Implications

The consequences of missed or incorrect Lynch syndrome diagnosis are significant:

• Individuals with Lynch syndrome have substantially increased lifetime risks for colorectal cancer (13% for males, 12% for females by age 80) and endometrial cancer (13% by age 80) compared to general population risks (6.6%, 4.7%, and 2.4%, respectively) 5

• Early detection enables effective cancer prevention through appropriate surveillance (colonoscopy every 1-2 years) and consideration of risk-reducing surgeries 1, 6

• Lynch syndrome diagnosis has implications for family members who may also carry the mutation 1

Recommended Approach

For individuals concerned about Lynch syndrome risk:

1. Consult healthcare providers with expertise in cancer genetics

2. Undergo proper risk assessment using validated clinical tools and criteria

3. If indicated, proceed with clinical genetic testing ordered by healthcare providers

4. Follow appropriate surveillance protocols based on genetic testing results

Consumer genomic tools like Promethease should not be relied upon for medical decisions regarding Lynch syndrome risk, as they may miss critical variants or provide misleading information that could negatively impact morbidity and mortality outcomes.