Lynch syndrome (LS), caused by a pathogenic variant (PV) in a DNA mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2), is associated with an increased risk of several cancers, particularly colorectal cancer (CRC) and endometrial cancer (EC). Early and appropriate surveillance is essential, but international guidelines diverge, notably due to imprecise risk estimates.
The aim of this study was to refine cancer risk estimates among carriers of MMR gene PVs in order to contribute to the updating of surveillance recommendations.

A search was conducted in PubMed on December 31, 2024, using the keywords “risk” AND “Lynch syndrome.” Original articles estimating cumulative cancer risk (penetrance) to age 70 in carriers of MMR gene PVs were included. In accordance with MOOSE guidelines, fixed-effects meta-analyses (n = 2 estimates) and random-effects meta-analyses (n > 2 estimates) were performed by gene, sex, cancer site, study design (retrospective family studies (RFS), prospective cohorts (PC), or population-based case–control studies (PBCC)), and methodology (with or without correction for ascertainment bias). Two authors independently assessed study eligibility and extracted relevant data.

Among the 33 included articles, the majority were RFS (n = 31), with one PC and one PBCC. Penetrance estimates varied by gene, study type, and methodology. Meta-analyses of RFS showed lower CRC risks at age 40 for carriers of MSH6 (0.4% [0.1–1.3] in women; 1.6% [0.9–2.6] in men) and PMS2 variants (0.3% [0.1–1.3] in women; 1.0% [0.4–2.3] in men), compared with MLH1 (3.1% [1.8–5.3] in women; 4.7% [2.7–8.1] in men) and MSH2 (4.4% [2.7–7.0] in women; 5.4% [3.4–8.5] in men).
For EC, risks at age 50 were 8.3% [5.1–13.4], 8.7% [3.8–18.7], 5.2% [2.3–11.2], and 3.0% [1.0–8.0] for MLH1, MSH2, MSH6, and PMS2 respectively.
For ovarian cancer, risks at age 40 were 1.2% [0.6–2.7] for MLH1 and 0.9% [0.5–1.8] for MSH2. Few studies evaluated other Lynch-associated cancers, highlighting the need for additional data.

This is the first systematic review and meta-analysis providing cancer risk estimates by cancer site, gene, and study type. These results may support revisions to surveillance recommendations for LS carriers, such as initiating colonoscopy at ages 30–35 for MSH6 and PMS2 carriers, postponing hysterectomy until after age 50 for PMS2 carriers, and delaying oophorectomy until after age 45 for all MMR PV carriers.