MSH6 gene: Lynch syndrome cancer risk, and why the estimates vary

The MSH6 gene, on chromosome 2 at 2p16.3, makes a protein that pairs with MSH2 to spot copying mistakes in DNA. A harmful change in one copy of MSH6 causes Lynch syndrome. MSH6 variants account for 12–35% of Lynch cases, and MSH6 and PMS2 are the most prevalent Lynch genes in the population. ^[1,9]

MSH6 and MSH2 form MutS alpha. NCBI lists the aliases GTBP, HNPCC5, LYNCH5 and MMRCS3. About 1 in 1,000 people in the United States carries an MSH6 variant, according to FORCE citing NIH All of Us; Lynch syndrome overall affects about 1 in 280–600 people. ^[1,4,9]

“MSH-6” is also the name of a microphone product; this page concerns the inherited human gene. Read the Lynch syndrome overview.

MSH6 variants cause Lynch syndrome by switching off one working copy of a DNA repair gene. The cell repairs DNA normally until a later second hit disables the remaining copy; copying errors then accumulate in that tissue. MSH6-deficient tumours show fewer insertion and deletion errors, so microsatellite tests can read as only mildly unstable. ^[1,11,12]

This is a loss-of-function mechanism. ClinGen classified the MSH6–Lynch syndrome relationship as Definitive on July 5, 2023. Pathogenicity is assessed with ACMG/AMP principles and the ClinGen MSH6 Variant Curation Expert Panel specification. IHC may be more sensitive than MSI alone for MSH6-deficient tumours. ^[1,7,10,15]

People with a pathogenic MSH6 variant have a lower colorectal cancer risk than MLH1 or MSH2 carriers, but their endometrial cancer risk is as high as with MLH1. NCCN Version 1.2026 gives 10–44% lifetime colorectal and 16–49% endometrial risk. GeneReviews reports 10% in women and 13% in men for colon cancer and 32% for endometrial cancer by age 65. ^[1,2,4]

Cumulative risk through age 65

Source: GeneReviews Table 3, updated September 17, 2026, using PLSD data from 8,500 carriers and 71,713 follow-up years. ^[1]

NCCN lifetime ranges

NCCN Versions 1.2026 and 1.2027 as reproduced by FORCE on September 24, 2026. ^[2,3,4]

Why MSH6 estimates differ

Estimates spread because studies select different cohorts, adjust for ascertainment differently, stop at different ages and have small numbers for rarer cancers. The Dutch study also estimated ovarian risk at 6.4%, urinary-tract risk at 10.1% in men and 4.1% in women, and biliary risk around 4–5%; it found no increased prostate or breast risk. ^[1,6]

PLSD reported median onset at 60.0 years for endometrial cancer and 55.1 in men and 60.1 in women for colorectal cancer, with wide confidence intervals. Not everyone develops cancer because penetrance remains below 100%. For sex-specific context, read about endometrial and ovarian cancer in Lynch syndrome. ^[1,5]

MSH6 carries a lower and later-onset colorectal cancer risk than MLH1 or MSH2, but the same endometrial risk as MLH1 at age 65. PLSD estimates colon cancer by 65 at 10% in women and 13% in men for MSH6, against 36% and 48% for MLH1. ^[1]

“Lower risk” applies to the colon, not the uterus. PMS2 estimates rest on 549 carriers and have more uncertainty. Compare the MLH1 gene, MSH2 gene and PMS2 gene. ^[1]

On a genetic test report, “MSH6 positive” means a pathogenic or likely pathogenic variant was found in MSH6, which establishes Lynch syndrome. On a tumour pathology report, “MSH6 positive” usually means the MSH6 protein is present on staining, the normal result. A variant of uncertain significance neither confirms nor rules out Lynch syndrome. ^[1,10]

Pathogenic and likely pathogenic results are managed alike under ACMG/AMP classification. A germline result starts counselling and confirmatory clinical testing; it is not a diagnosis of cancer. Because MSH6-deficient tumours can be MSI-low, IHC may be more sensitive than MSI alone. Read about tumour MSI and IHC testing. The “present = normal” wording requires pathology review before publication. ^[1,10,11,12]

An MSH6 variant is inherited in an autosomal dominant pattern: each child of a carrier has a 50% chance of inheriting it, and it does not skip generations. Relatives can be tested for the one known family variant. A child who inherits an MSH6 variant from both parents has a separate, far more severe condition. ^[1,4]

Two pathogenic MSH6 variants can cause constitutional mismatch repair deficiency (CMMRD). Most first tumours occur before 18, and about half of affected children develop cancer by 10. When both parents carry an MSH6 variant, each child has a 25% chance of CMMRD. ClinGen classifies MSH6–CMMRD as Definitive and adult Lynch actionability as Definitive; paediatric actionability for monoallelic Lynch syndrome has insufficient evidence. ^[1,7,13]

For people with an MSH6 variant, NCCN Version 1.2026 advises colonoscopy every 1–3 years starting at age 30–35, later than the 20–25 start for MLH1 and MSH2. GeneReviews gives the same MSH6 schedule. Endometrial biopsy is discussed every 1–2 years from 30–35. Plans are individual and set with a genetic counsellor or clinician. ^[1,2,4]

Guidance is not uniform. eviQ recommends colonoscopy every 1–2 years from 35, while the 2025 Dutch study concluded that screening could start at 35–40. Current NCCN and GeneReviews guidance is shown in the table. Read the detailed colonoscopy schedule and aspirin guide and the guide to endometrial and ovarian cancer in Lynch syndrome. ^[1,2,6,13]

MSH6 variants are found by DNA sequencing, with deletion and duplication analysis added, usually inside a multigene panel. Sequencing detects at least 90% of MSH6 pathogenic variants and deletion/duplication analysis up to 10%. Because MSH6-deficient tumours can be mildly unstable, MSI alone can miss them and staining may be more sensitive. A tumour test is a different test. ^[1,11,12]

Germline testing asks what can be inherited; tumour MSI and IHC examine cancer tissue. A potentially important finding requires confirmation and counselling. Read how Lynch syndrome genetic testing works and tumour MSI and IHC testing. ^[1]