Hereditary nonpolyposis colon cancer: genes and variants

Genes linked to Hereditary nonpolyposis colon cancer

• 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 9 uncertain variants in MLH1 are linked to Hereditary nonpolyposis colon cancer.

• 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.

  4 disease-causing and 1 uncertain variants in PMS2 are linked to Hereditary nonpolyposis colon cancer.

• 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.

  3 disease-causing and 0 uncertain variants in MSH6 are linked to Hereditary nonpolyposis colon cancer.

• CHEK2: Serine/threonine-protein kinase Chk2

  It propagates DNA-damage checkpoint signals to proteins controlling cell-cycle arrest, repair, and apoptosis. Germline loss-of-function variants confer moderate cancer susceptibility, especially for breast cancer, while risk estimates depend on the specific allele and family context.

  1 disease-causing and 20 uncertain variants in CHEK2 are linked to Hereditary nonpolyposis colon cancer.

• 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 1 uncertain variants in MSH2 are linked to Hereditary nonpolyposis colon cancer.

• CTNNA1: Catenin alpha-1

  It links cadherin-catenin adhesion complexes to the actin cytoskeleton and helps maintain epithelial integrity and tissue architecture. Germline loss-of-function variants can predispose to diffuse gastric cancer, while biallelic variants can cause severe epithelial and skin disease.

  0 disease-causing and 14 uncertain variants in CTNNA1 are linked to Hereditary nonpolyposis colon cancer.

Weakly linked (only a few uncertain records): CDKN1B and FAN1.

Known disease-causing variants in Hereditary nonpolyposis colon cancer

Which prediction tools work for Hereditary nonpolyposis colon cancer

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• SIFT: 87 out of 100
• PolyPhen-2: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

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

Diseases related to Hereditary nonpolyposis colon cancer

• Colorectal cancer, also linked to CHEK2, CTNNA1, MLH1, MSH2 and 1 more
• Breast and/or ovarian cancer, also linked to CHEK2, MLH1, MSH2, MSH6 and 1 more
• Lynch syndrome, also linked to MLH1, MSH2, MSH6 and PMS2
• Hereditary nonpolyposis colorectal neoplasms, also linked to MLH1, MSH2, MSH6 and PMS2
• Gastric cancer, also linked to CHEK2, MLH1, MSH6 and PMS2
• Mismatch repair cancer syndrome, 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
• Hereditary breast ovarian cancer syndrome, also linked to CHEK2 and MLH1
• Muir-Torré syndrome, also linked to MLH1 and MSH2
• Lynch-like syndrome, also linked to MLH1 and MSH6
• Li-Fraumeni syndrome, also linked to CHEK2

Frequently asked questions

Which genes are linked to Hereditary nonpolyposis colon cancer?

In CATVariant, Hereditary nonpolyposis colon cancer is linked to 6 analyzed proteins: MLH1 (DNA mismatch repair protein Mlh1), PMS2 (Mismatch repair endonuclease PMS2), MSH6 (DNA mismatch repair protein Msh6), CHEK2 (Serine/threonine-protein kinase Chk2), MSH2 (DNA mismatch repair protein Msh2) and CTNNA1 (Catenin alpha-1).

How many genetic variants are linked to Hereditary nonpolyposis colon cancer?

63 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 46 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hereditary nonpolyposis colon cancer look disease-causing?

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

Which variant effect predictor works best for Hereditary nonpolyposis colon cancer?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 10 disease-causing and 340 harmless variants).

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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