Colorectal cancer, hereditary nonpolyposis, type 6: genes and variants

Genes linked to Colorectal cancer, hereditary nonpolyposis, type 6

• 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.

  17 disease-causing and 176 uncertain variants in MLH1 are linked to Colorectal cancer, hereditary nonpolyposis, type 6.

• TGFBR2: TGF-beta receptor type-2

  It binds TGF-beta ligands and activates TGFBR1 to initiate canonical and noncanonical signaling. Germline pathogenic variants cause Loeys-Dietz syndrome type 2, while somatic loss can remove growth-suppressive TGF-beta responses in cancer.

  0 disease-causing and 19 uncertain variants in TGFBR2 are linked to Colorectal cancer, hereditary nonpolyposis, type 6.

• MLH3: DNA mismatch repair protein Mlh3

  It partners with other mismatch-repair proteins and also participates in meiotic crossover formation. Biallelic or monoallelic variants have been investigated in cancer predisposition, but the clinical significance of many MLH3 variants remains less firmly established than for core Lynch-syndrome genes.

  0 disease-causing and 14 uncertain variants in MLH3 are linked to Colorectal cancer, hereditary nonpolyposis, type 6.

Known disease-causing variants in Colorectal cancer, hereditary nonpolyposis, type 6

Which prediction tools work for Colorectal cancer, hereditary nonpolyposis, type 6

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

• CATVariant: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 88 out of 100
• ESM1b (LLR): 88 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 74 out of 100
• MutPred2: 69 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 Colorectal cancer, hereditary nonpolyposis, type 6 variants (64 disease-causing).
• Hereditary nonpolyposis colorectal neoplasms is also caused by MLH1 variants; they fall mostly in different places as the Colorectal cancer, hereditary nonpolyposis, type 6 variants (51 disease-causing).
• Muir-Torré syndrome is also caused by MLH1 variants; they fall mostly in different places as the Colorectal cancer, hereditary nonpolyposis, type 6 variants (4 disease-causing).
• Hereditary nonpolyposis colon cancer is also caused by MLH1 variants; they fall mostly in different places as the Colorectal cancer, hereditary nonpolyposis, type 6 variants (4 disease-causing).
• Mismatch repair cancer syndrome is also caused by MLH1 variants; they fall mostly in different places as the Colorectal cancer, hereditary nonpolyposis, type 6 variants (4 disease-causing).

Diseases related to Colorectal cancer, hereditary nonpolyposis, type 6

• Lynch syndrome, also linked to MLH1 and MLH3
• Colorectal cancer, also linked to MLH1 and MLH3
• Endometrial carcinoma, also linked to MLH1 and MLH3
• Familial thoracic aortic aneurysm and aortic dissection, also linked to TGFBR2
• Marfan syndrome, also linked to TGFBR2
• Ehlers-Danlos syndrome, also linked to TGFBR2
• Hereditary nonpolyposis colorectal neoplasms, also linked to MLH1
• Loeys-Dietz syndrome, also linked to TGFBR2
• Ovarian cancer, also linked to MLH1
• Gastric cancer, also linked to MLH1
• Hereditary nonpolyposis colon cancer, also linked to MLH1
• Hereditary breast ovarian cancer syndrome, also linked to MLH1

Frequently asked questions

Which genes are linked to Colorectal cancer, hereditary nonpolyposis, type 6?

In CATVariant, Colorectal cancer, hereditary nonpolyposis, type 6 is linked to 3 analyzed proteins: MLH1 (DNA mismatch repair protein Mlh1), TGFBR2 (TGF-beta receptor type-2) and MLH3 (DNA mismatch repair protein Mlh3).

How many genetic variants are linked to Colorectal cancer, hereditary nonpolyposis, type 6?

232 variants: 17 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 209 are of uncertain significance or have conflicting reports.

Which uncertain variants in Colorectal cancer, hereditary nonpolyposis, type 6 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 Colorectal cancer, hereditary nonpolyposis, type 6?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 17 disease-causing and 19 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.

Download every variant as CSV · Browse all diseases · Methods · About the Center