Molecular profiling of a colorectal carcinoma reveals high microsatellite instability (MSI-H) and loss of MLH1 protein expression by immunohistochemistry, but BRAF V600E mutation is absent and MLH1 promoter methylation is absent. Which germline syndrome is most likely?

• A Sporadic MSI-H colorectal cancer with CIMP phenotype
• B Familial adenomatous polyposis with APC mutation
• C MYH-associated polyposis with MUTYH biallelic mutation
• D Lynch syndrome due to germline MLH1 mutation ✓

Explanation

The absence of BRAF V600E mutation and absence of MLH1 promoter methylation in an MSI-H tumor with lost MLH1 protein is the diagnostic fingerprint of Lynch syndrome with germline MLH1 mutation. Sporadic MSI-H CRC typically shows BRAF V600E mutation and MLH1 promoter hypermethylation (CIMP phenotype). FAP shows chromosomal instability (CIN), not MSI. MUTYH-associated polyposis involves MUTYH base-excision repair mutations but generally does not produce MSI-H.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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