Mismatch repair cancer syndrome: genes and variants

Genes linked to Mismatch repair cancer syndrome

• MLH1: DNA mismatch repair protein Mlh1

  The protein partners with PMS2 to form MutL alpha, a core complex in post-replicative DNA mismatch repair. By helping correct copying errors in DNA, MLH1 protects genome stability, and inherited MLH1 variants are a major cause of Lynch syndrome.

  4 disease-causing and 35 uncertain variants in MLH1 are linked to Mismatch repair cancer syndrome.

• PMS2: Mismatch repair endonuclease PMS2

  Together with MLH1, it provides endonuclease activity needed to complete DNA mismatch repair after replication errors are recognized. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants cause constitutional mismatch-repair deficiency.

  1 disease-causing and 90 uncertain variants in PMS2 are linked to Mismatch repair cancer syndrome.

• MSH6: DNA mismatch repair protein Msh6

  Together with MSH2, it recognizes single-base mismatches and small insertion-deletion loops during DNA replication and initiates mismatch repair. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants can cause constitutional mismatch-repair deficiency.

  1 disease-causing and 33 uncertain variants in MSH6 are linked to Mismatch repair cancer syndrome.

• MSH2: DNA mismatch repair protein Msh2

  The protein forms mismatch-recognition complexes with MSH6 or MSH3 that detect base mismatches and insertion-deletion loops in DNA. This first step of mismatch repair helps preserve genome integrity, and inherited MSH2 variants are associated with Lynch syndrome.

  1 disease-causing and 21 uncertain variants in MSH2 are linked to Mismatch repair cancer syndrome.

Known disease-causing variants in Mismatch repair cancer syndrome

Same protein, different disease

• Lynch syndrome is also caused by MLH1 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (64 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by MLH1 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (51 disease-causing).
• Colorectal cancer, hereditary nonpolyposis, type 6 is also caused by MLH1 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (17 disease-causing).
• Hereditary nonpolyposis colon cancer is also caused by MLH1 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (4 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by PMS2 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (12 disease-causing).
• Lynch syndrome is also caused by PMS2 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (11 disease-causing).
• Hereditary nonpolyposis colon cancer is also caused by PMS2 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (4 disease-causing).
• Lynch syndrome is also caused by MSH2 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (22 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by MSH2 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (12 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by MSH6 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (14 disease-causing).
• Lynch syndrome is also caused by MSH6 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (12 disease-causing).
• Hereditary nonpolyposis colon cancer is also caused by MSH6 variants; they fall mostly in different places as the Mismatch repair cancer syndrome variants (3 disease-causing).

Diseases related to Mismatch repair cancer syndrome

• Lynch syndrome, also linked to MLH1, MSH2, MSH6 and PMS2
• Hereditary nonpolyposis colorectal neoplasms, also linked to MLH1, MSH2, MSH6 and PMS2
• Hereditary nonpolyposis colon cancer, also linked to MLH1, MSH2, MSH6 and PMS2
• Breast and/or ovarian cancer, also linked to MLH1, MSH2, MSH6 and PMS2
• Endometrial carcinoma, also linked to MLH1, MSH2, MSH6 and PMS2
• Ovarian cancer, also linked to MLH1, MSH2 and MSH6
• Colorectal cancer, also linked to MLH1, MSH2 and MSH6
• Gastric cancer, also linked to MLH1, MSH6 and PMS2
• Muir-Torré syndrome, also linked to MLH1 and MSH2
• Lynch-like syndrome, also linked to MLH1 and MSH6
• Colorectal cancer, hereditary nonpolyposis, type 6, also linked to MLH1
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to MSH2

Frequently asked questions

Which genes are linked to Mismatch repair cancer syndrome?

In CATVariant, Mismatch repair cancer syndrome is linked to 4 analyzed proteins: MLH1 (DNA mismatch repair protein Mlh1), PMS2 (Mismatch repair endonuclease PMS2), MSH6 (DNA mismatch repair protein Msh6) and MSH2 (DNA mismatch repair protein Msh2).

How many genetic variants are linked to Mismatch repair cancer syndrome?

187 variants: 7 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 179 are of uncertain significance or have conflicting reports.

Which uncertain variants in Mismatch repair cancer syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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