Familial adenomatous polyposis: genes and variants

Genes linked to Familial adenomatous polyposis

• MUTYH: Adenine DNA glycosylase

  It removes adenines incorrectly paired with oxidized guanine, preventing characteristic G:C-to-T:A mutations during base-excision repair. Biallelic loss-of-function variants cause MUTYH-associated polyposis and substantially increase colorectal-cancer risk.

  27 disease-causing and 995 uncertain variants in MUTYH are linked to Familial adenomatous polyposis.

• APC: Adenomatous polyposis coli protein

  A tumor-suppressor protein that promotes the removal of beta-catenin and helps keep Wnt signaling under control. It also organizes microtubules and actin in the cell, and inherited APC disruption is strongly associated with familial adenomatous polyposis and colorectal tumor risk.

  4 disease-causing and 2,091 uncertain variants in APC are linked to Familial adenomatous polyposis.

• NTHL1: Endonuclease III-like protein 1

  It removes oxidized pyrimidines from DNA through base-excision repair and prevents accumulation of characteristic point mutations. Biallelic loss-of-function variants cause NTHL1 tumor syndrome with colorectal polyposis and increased risk of multiple malignancies.

  1 disease-causing and 154 uncertain variants in NTHL1 are linked to Familial adenomatous polyposis.

• MSH3: DNA mismatch repair protein Msh3

  Together with MSH2, it recognizes larger insertion-deletion loops and certain DNA secondary structures during mismatch repair. Variation can modify the behavior of repeat-expansion disorders, while biallelic loss has been associated with a recessive adenomatous-polyposis phenotype.

  0 disease-causing and 115 uncertain variants in MSH3 are linked to Familial adenomatous polyposis.

• TSC2: Tuberin

  Together with TSC1, it inactivates RHEB and restrains mTORC1 when growth conditions are unfavorable. Loss-of-function variants cause tuberous sclerosis complex with hamartomas and tumors affecting the brain, kidneys, skin, heart, lungs, and other organs.

  0 disease-causing and 0 uncertain variants in TSC2 are linked to Familial adenomatous polyposis.

Weakly linked (only a few uncertain records): VDR.

Known disease-causing variants in Familial adenomatous polyposis

Which prediction tools work for Familial adenomatous polyposis

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

• AlphaMissense: 88 out of 100
• MetaLR: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 85 out of 100
• MutPred2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 84 out of 100

Same protein, different disease

• Ovarian cancer is also caused by APC variants; they fall mostly in different places as the Familial adenomatous polyposis variants (4 disease-causing).

Diseases related to Familial adenomatous polyposis

• Colorectal cancer, also linked to APC, MUTYH and NTHL1
• Ovarian cancer, also linked to APC and TSC2
• Gastric cancer, also linked to APC and MUTYH
• Hepatocellular carcinoma, also linked to APC and TSC2
• Inherited polyposis and early onset colorectal cancer - germline testing, also linked to MUTYH and NTHL1
• Classic or attenuated familial adenomatous polyposis, also linked to APC and MUTYH
• Tuberous sclerosis, also linked to TSC2
• Isolated focal cortical dysplasia type II, also linked to TSC2
• Pilomatrixoma, also linked to MUTYH
• Endometrial carcinoma, also linked to MSH3
• Tuberous sclerosis syndrome, also linked to TSC2
• Neoplasm of stomach, also linked to MUTYH

Frequently asked questions

Which genes are linked to Familial adenomatous polyposis?

In CATVariant, Familial adenomatous polyposis is linked to 5 analyzed proteins: MUTYH (Adenine DNA glycosylase), APC (Adenomatous polyposis coli protein), NTHL1 (Endonuclease III-like protein 1), MSH3 (DNA mismatch repair protein Msh3) and TSC2 (Tuberin).

How many genetic variants are linked to Familial adenomatous polyposis?

3,576 variants: 32 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3,356 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial adenomatous polyposis 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 Familial adenomatous polyposis?

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 29 disease-causing and 120 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