Fanconi anemia: genes and variants

Genes linked to Fanconi anemia

• FANCA: Fanconi anemia group A protein

  It helps assemble the Fanconi-anemia core complex that monoubiquitinates FANCD2 and FANCI after DNA interstrand crosslinks stall replication. Biallelic loss-of-function variants are the most common cause of Fanconi anemia, with bone-marrow failure and cancer predisposition.

  15 disease-causing and 895 uncertain variants in FANCA are linked to Fanconi anemia.

• FANCD2: Fanconi anemia group D2 protein

  Its damage-induced monoubiquitination recruits and coordinates nucleases and homologous-recombination factors at stalled replication forks and interstrand crosslinks. Biallelic loss-of-function variants cause Fanconi anemia group D2.

  5 disease-causing and 476 uncertain variants in FANCD2 are linked to Fanconi anemia.

• FANCC: Fanconi anemia group C protein

  It contributes to activation of the FANCD2-FANCI DNA-repair pathway after replication-blocking lesions. Biallelic loss-of-function variants cause Fanconi anemia group C, with chromosome instability, marrow failure, congenital abnormalities, and elevated cancer risk.

  1 disease-causing and 360 uncertain variants in FANCC are linked to Fanconi anemia.

• RAD51C: DNA repair protein RAD51 homolog 3

  It participates in RAD51-paralog complexes that promote homologous-recombination repair and restart damaged replication forks. Heterozygous loss-of-function variants increase ovarian and breast-cancer risk, while biallelic variants can cause Fanconi anemia.

  0 disease-causing and 0 uncertain variants in RAD51C are linked to Fanconi anemia.

• BRCA2: Breast cancer type 2 susceptibility protein

  It loads RAD51 onto damaged DNA to enable homologous recombination and also protects stressed replication forks from degradation. Germline loss-of-function variants strongly predispose to breast, ovarian, prostate, pancreatic, and other cancers.

  0 disease-causing and 0 uncertain variants in BRCA2 are linked to Fanconi anemia.

• BRIP1: Fanconi anemia group J protein

  It unwinds DNA structures and works with BRCA1 and the Fanconi-anemia pathway to repair damaged replication intermediates and interstrand crosslinks. Biallelic loss causes Fanconi anemia group J, while heterozygous loss-of-function variants increase ovarian-cancer risk.

  0 disease-causing and 0 uncertain variants in BRIP1 are linked to Fanconi anemia.

• ERCC4: DNA repair endonuclease XPF

  Together with ERCC1, it makes structure-specific DNA incisions required for nucleotide-excision repair and interstrand-crosslink repair. Biallelic pathogenic variants can cause xeroderma pigmentosum, Fanconi anemia, or severe progeroid DNA-repair disease.

  0 disease-causing and 0 uncertain variants in ERCC4 are linked to Fanconi anemia.

• PALB2: Partner and localizer of BRCA2

  It physically links BRCA1 and BRCA2 and helps recruit BRCA2-RAD51 repair machinery to DNA double-strand breaks. Heterozygous loss-of-function variants substantially increase breast and pancreatic cancer risk, while biallelic variants cause Fanconi anemia subtype N.

  0 disease-causing and 0 uncertain variants in PALB2 are linked to Fanconi anemia.

• POLG: DNA polymerase subunit gamma-1

  It replicates and repairs mitochondrial DNA and is therefore essential for maintaining mitochondrial genome copy number and integrity. Pathogenic variants cause a broad spectrum including Alpers syndrome, progressive external ophthalmoplegia, epilepsy, ataxia, neuropathy, and liver disease.

  0 disease-causing and 0 uncertain variants in POLG are linked to Fanconi anemia.

• RAD51: DNA repair protein RAD51 homolog 1

  0 disease-causing and 0 uncertain variants in RAD51 are linked to Fanconi anemia.

• XRCC2: DNA repair protein XRCC2

  It acts with other RAD51 paralogs to assemble and stabilize homologous-recombination repair machinery at DNA double-strand breaks. Biallelic loss-of-function variants can cause Fanconi-anemia-like chromosome-instability disease, while heterozygous cancer-risk associations are less certain.

  0 disease-causing and 0 uncertain variants in XRCC2 are linked to Fanconi anemia.

Known disease-causing variants in Fanconi anemia

Which prediction tools work for Fanconi anemia

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

• REVEL: 99 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100
• CADD: 94 out of 100
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 87 out of 100

Same protein, different disease

• Fanconi anemia complementation group A is also caused by FANCA variants; they fall mostly in different places as the Fanconi anemia variants (38 disease-causing).

Diseases related to Fanconi anemia

• Ovarian cancer, also linked to BRCA2, BRIP1, ERCC4, FANCA and 3 more
• Hereditary breast ovarian cancer syndrome, also linked to BRCA2, BRIP1, FANCC, FANCD2 and 2 more
• Acute myeloid leukemia, also linked to ERCC4, FANCA, FANCC, FANCD2 and 1 more
• Breast-ovarian cancer, familial, susceptibility to, 1, also linked to BRCA2, BRIP1, PALB2 and RAD51C
• Gastric cancer, also linked to BRIP1, PALB2 and RAD51C
• Fanconi anemia complementation group A, also linked to FANCA and FANCC
• Familial cancer of breast, also linked to BRIP1 and PALB2
• Ovarian neoplasm, also linked to BRCA2 and BRIP1
• Breast and/or ovarian cancer, also linked to BRIP1 and RAD51C
• Familial ovarian cancer, also linked to BRIP1 and RAD51C
• Familial pancreatic carcinoma, also linked to BRCA2 and PALB2
• Hereditary spastic paraplegia, also linked to POLG

Frequently asked questions

Which genes are linked to Fanconi anemia?

In CATVariant, Fanconi anemia is linked to 11 analyzed proteins: FANCA (Fanconi anemia group A protein), FANCD2 (Fanconi anemia group D2 protein), FANCC (Fanconi anemia group C protein), RAD51C (DNA repair protein RAD51 homolog 3), BRCA2 (Breast cancer type 2 susceptibility protein), BRIP1 (Fanconi anemia group J protein) and 5 more.

How many genetic variants are linked to Fanconi anemia?

1,915 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,731 are of uncertain significance or have conflicting reports.

Which uncertain variants in Fanconi anemia 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 Fanconi anemia?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 20 disease-causing and 262 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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