MSH6-Associated Lynch Syndrome Cancer Risks
MSH6 mutation carriers have substantially lower colorectal cancer risk compared to MLH1/MSH2 carriers, with a cumulative lifetime risk of 10-22% by age 70, but women face a notably high endometrial cancer risk of 17-71%. 1
Colorectal Cancer Risk
The colorectal cancer risk in MSH6 carriers is approximately one-third lower than MLH1/MSH2 carriers, with later age of onset. 1
- Males: 22% cumulative risk by age 70 1
- Females: 10% cumulative risk by age 70 1
- Combined risk: 18% for both sexes by age 70 1
- Mean age at diagnosis: 54-63 years, which is 3-5 years later than MLH1/MSH2 carriers 1, 2
- Risk by age 40: Remains very low at <2% 3, 4
The most recent high-quality data from 2025 confirms these estimates, showing 36% risk in males and 21% in females by age 80, with minimal risk before age 40 (0.2% in males, 0.9% in females). 3
Endometrial Cancer Risk
Unlike colorectal cancer, endometrial cancer risk is NOT lower in MSH6 carriers—in fact, it may be higher than other Lynch syndrome genes. 1
- Cumulative risk by age 70: 17-71% 1
- Mean age at diagnosis: 54-57 years 1
- Risk by age 50: Approximately 5.2% 4
- Lifetime risk by age 80: 23% 3
MSH6 female carriers demonstrate the highest endometrial cancer risk among all Lynch syndrome genes, with one study showing 61% cumulative risk by age 70. 2 This creates a distinct risk profile where endometrial cancer becomes the predominant concern for women with MSH6 mutations.
Other Cancer Risks
MSH6 carriers have elevated risks for several extracolonic cancers beyond endometrium: 3
- Ovarian cancer: 6.4% lifetime risk (HR 5.58) 3
- Urinary tract cancers: 10.1% in males, 4.1% in females (HR 2.52) 3
- Biliary tract cancers: 4.9% in males, 4.2% in females (HR 2.76) 3
- Gastric cancer: 0.2-13% depending on population (higher in Asian populations) 1
- Small bowel cancer: 0.4-12% 1
No increased risk has been demonstrated for breast or prostate cancer in MSH6 carriers. 5, 3
Critical Clinical Distinctions
MSH6-associated Lynch syndrome presents a unique genotype-phenotype correlation that should fundamentally alter surveillance strategies: 2
- Later onset of colorectal cancer allows for delayed colonoscopy initiation (age 30-35 rather than 20-25 years) 2, 3, 4
- Higher endometrial cancer risk makes prophylactic hysterectomy more compelling for MSH6 female carriers compared to other Lynch genes 2
- Tumors may not show classic microsatellite instability patterns, complicating diagnosis 6
Important Caveats
Risk estimates vary significantly based on ascertainment method—families identified in high-risk clinics show higher penetrance than population-based studies. 1 The 2025 meta-analysis stratifying by study design (retrospective family studies vs. prospective cohort vs. population-based) provides the most nuanced estimates. 4
Age-specific risks are critical for counseling: The risk before age 40 is minimal for colorectal cancer (<2%), which supports delayed surveillance initiation compared to MLH1/MSH2 carriers. 3, 4 However, endometrial cancer risk begins accumulating earlier, with 5.2% risk by age 50. 4
Geographic variation exists for gastric cancer risk: While Western populations show 2-4% risk, Asian populations (Korean, Chinese) demonstrate up to 30% lifetime gastric cancer risk in Lynch syndrome generally, though MSH6-specific data for these populations is limited. 1