Blood Testing for Lynch Syndrome
Yes, there is blood testing available for Lynch syndrome, but it requires a specific sequential approach: initial tumor tissue screening (not blood) followed by germline genetic testing of blood when indicated.
Diagnostic Algorithm
The diagnosis of Lynch syndrome follows a two-stage process that ultimately includes blood testing, but does not start with blood work 1, 2:
Stage 1: Tumor Tissue Screening (Required First)
For all patients with colorectal cancer, tumor tissue must first be tested using either 1:
- Immunohistochemistry (IHC) - detects presence/absence of MLH1, MSH2, MSH6, or PMS2 proteins
- Microsatellite instability (MSI) testing - identifies high MSI characteristic of Lynch syndrome tumors
This is a strong recommendation for universal tumor screening in all colorectal cancers regardless of age 1.
Stage 2: Reflex Testing for MLH1 Loss
If IHC shows MLH1 protein loss, perform second-stage tumor testing before proceeding to blood work 1:
- BRAF V600E mutation testing, OR
- MLH1 promoter hypermethylation testing
This step is critical because approximately 75% of MLH1-absent tumors are sporadic (not Lynch syndrome). If either test is positive, Lynch syndrome is extremely unlikely and blood testing is not needed 1.
Stage 3: Germline Blood Testing
Blood-based germline genetic testing is indicated when 2:
Definite indications:
- Abnormal tumor IHC/MSI results (after ruling out sporadic causes for MLH1 loss)
- Known Lynch syndrome pathogenic variant in the family
- Personal history of Lynch-related cancer diagnosed <50 years old
- Multiple Lynch-related cancers in patient or family members
- ≥5% risk on prediction models (PREMM5, MMRpro, MMRpredict)
The blood test specifically looks for germline pathogenic variants in:
- MLH1
- MSH2
- MSH6
- PMS2
- EPCAM (deletions causing MSH2 silencing) 2
Key Clinical Pitfalls
Common mistake: Ordering germline blood testing without tumor screening first. This approach is inefficient and costly, as most abnormal tumors are sporadic rather than hereditary 1.
Important caveat: For individuals with strong family history meeting Amsterdam criteria but no personal cancer history, you may proceed directly to germline blood testing using risk prediction models (PREMM score ≥2.5-5%) 2.
Timing consideration: In the English registry study, median time from cancer diagnosis to germline testing was 315 days, highlighting significant delays in the diagnostic pathway 3. Streamlined referral systems are essential.
Emerging Technologies
Research suggests future blood-based screening may become possible through detection of MMR protein deficiency in fresh lymphocytes, potentially allowing population-based screening before cancer develops 4. However, this remains investigational and is not part of current clinical guidelines.
The bottom line: While blood testing (germline genetic testing) is the definitive diagnostic test for Lynch syndrome, it should only be performed after appropriate tumor tissue screening or in high-risk individuals meeting specific clinical criteria 1, 2.