MSH6 germline loss-of-function in crc produces dMMR/MSI-H phenotype. Pan-tumor MSI-H ICI...
Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.
| ID | BMA-MSH6-GERMLINE-CRC |
|---|---|
| Type | Actionability |
| Status | reviewed 2026-04-27 | pending_clinical_signoff | actionability review required |
| Diseases | DIS-CRC |
| Sources | SRC-CIVIC SRC-ESMO-COLON-2024 SRC-NCCN-COLON-2025 |
Actionability Facts
| Biomarker | BIO-DMMR-IHC |
|---|---|
| Variant | MSH6 germline loss-of-function (dMMR / MSI-H) |
| Disease | DIS-CRC |
| ESCAT tier | IA |
| Recommended combinations | pembrolizumab monotherapy (1L mCRC dMMR, KEYNOTE-177), dostarlimab (neoadjuvant rectal dMMR, off-label), nivolumab + ipilimumab (2L+ mCRC dMMR, CheckMate-142) |
| Contraindicated monotherapy | FOLFOX/FOLFIRI 1L in dMMR mCRC (inferior to ICI), adjuvant 5-FU monotherapy in stage II dMMR (no benefit, possibly harmful) |
| Evidence summary | MSH6 germline loss-of-function in crc produces dMMR/MSI-H phenotype. Pan-tumor MSI-H ICI eligibility (pembrolizumab per KEYNOTE-158, dostarlimab per GARNET) supersedes tumor-specific lines via tissue-agnostic FDA approval. 1L mCRC: pembrolizumab monotherapy (KEYNOTE-177) — mPFS 16.5 vs 8.2 mo vs chemo. Adjuvant ICI in stage III dMMR CRC under investigation; deferral of adjuvant 5-FU appropriate in stage II dMMR (chemoinsensitive). Neoadjuvant dostarlimab in dMMR rectal cancer → 100% cCR (Cercek 2022). |
Notes
Germline MSH6 loss → cascade testing mandatory (Lynch syndrome). Family meets Amsterdam/Bethesda criteria. Pan-tumor MSI-H ICI eligibility supersedes tumor- specific lines.
Used By
No reverse references found in the YAML corpus.