DiagnosisClinical DiagnosisRecommendations for diagnosis were agreed upon at a 2008 consensus conference [Eiler et al 2008; click for full text].Fanconi anemia (FA) is suspected in individuals with the following:Physical abnormalities including short stature; abnormal skin pigmentation (e.g., café au lait spots or hypopigmentation); malformations of the thumbs, forearms, skeletal system, eye, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. These findings are variable; approximately 25%-40% of individuals with Fanconi anemia have no physical abnormalities. Thus, the absence of physical abnormalities does NOT rule out the diagnosis of Fanconi anemia. Progressive bone marrow failure, manifest as thrombocytopenia, leukopenia, and anemia, typically presenting by age seven to eight years, often initially with either thrombocytopenia or leukopenia. Bone marrow, initially normocellular, becomes progressively hypoplastic with time. Adult-onset aplastic anemia, in which red cell macrocytosis and elevated hemoglobin F levels may be seen. Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). On occasion, MDS or AML is the initial manifestation. Solid tumors presenting at an atypically young age and in the absence of other risk factors. These tumors include squamous cell carcinomas of the head and neck, esophagus, and vulva; cervical cancer; and liver tumors (usually but not exclusively associated with treatment with oral androgens). Solid tumors may be the first manifestation of Fanconi anemia in individuals who have no birth defects and have not experienced bone marrow failure. Inordinate toxicities from chemotherapy or radiationTestingChromosomal breakage studies. The diagnosis of FA rests on cytogenetic testing for increased chromosomal breakage or rearrangement in the presence of diepoxybutane (DEB), a bifunctional DNA interstrand cross-linking agent [Auerbach 1993] or radial figures with mitomycin C (MMC) [Cervenka et al 1981]. The background rate of chromosomal breakage in control chromosomes is more variable with MMC; thus, some centers prefer to use DEB while other centers use both DEB and MMC. Peripheral blood is cultured with a T-cell mitogen, phytohemagglutinin, in the presence and absence of the cross-linking agent. A total of 50 cells in metaphase are scored and analyzed for chromosomal breakage as well as the formation of radials. Results are compared with those from normal control cells and FA-positive control cells.Cultures without the DNA clastogenic agent may be used to measure the spontaneous breakage rate. Results are reported as either the average number of breaks/cell or as x number of cells with 1,2,3...>8 breaks. The number of cells with radial forms is recorded. In response to DEB or MMC, individuals with FA show:Increased rates of spontaneous chromosomal breakage (may be seen in FA as well as other chromosomal breakage syndromes; see Differential Diagnosis) Increased breakage and radial forms that distinguish FA from other chromosomal breakage syndromes The increased sensitivity to DEB/MMC is present regardless of phenotype, congenital anomalies, or severity of the disease. Note: Interpretation of the results of the chromosomal breakage test may be complicated by mosaicism, defined as the presence of two populations of lymphocytes: one showing increased sensitivity to DEB/MMC and the other showing normal levels of chromosomal breakage in response to DEB/MMC. This normal cellular phenotype has been attributed to gene conversion events, back mutations, or compensatory deletions/insertions leading to selective advantage of the gene-corrected lymphocytes [Lo Ten Foe et al 1997, Waisfisz et al 1999, Gross et al 2002]. Lymphocyte mosaicism can develop in individuals initially found to be sensitive to DEB/MMC. These individuals may have a falsely normal DEB/MMC test. In individuals with a normal DEB/MMC test in whom a high degree of clinical suspicion of FA remains, DEB/MMC testing to establish the diagnosis could be performed on an alternative cell type, such as skin fibroblasts. Tabulation of the number of cells with chromosomal breaks and radials can assist in diagnosis in the presence of lymphocyte mosaicism. FA heterozygotes cannot be detected by the DEB/MMC test because their results are within the normal range.Other cytogenetic testing. Abnormal bone marrow cytogenetic findings may develop. Cytogenetic abnormalities can wax and wane or the patient may progress to myelodysplastic syndrome (MDS) and leukemia [Alter et al 2000]. Clonal amplifications of chromosome 3q26-q29 were reported in association with an increased risk of progression to MDS or acute myelogenous leukemia (AML) [Tonnies et al 2003, Cioc et al 2010]. Immunoblot assay of FANCD2 protein monoubiquitination. The Fanconi anemia proteins A, B, C, E, F, G, I, L, and M form the core complex required for the monoubiquitination of the downstream FANCD2 protein. FANCD2 protein monoubiquitination is essential for the functional integrity of the FA pathway as measured by resistance to MMC or DEB. Because FANCD2 protein monoubiquitination is intact in other bone marrow failure syndromes and chromosomal breakage syndromes tested to date [Shimamura et al 2002], evaluation of FANCD2 protein monoubiquitination by immunoblotting provides a rapid diagnostic test for Fanconi anemia. Note that the rare FA subtypes FA-D1 (BRCA2), FA-J (BACH1/BRIP1), and FA-N (PALB2) would be missed by this approach (because they are downstream of FANCD2), as might individuals with somatic mosaicism. Cell cycle arrest. MMC also induces cell cycle arrest in the G2 phase. Flow cytometric assessment of G2 arrest has been used diagnostically [Pulsipher et al 1998]. In this test, primary skin fibroblasts are exposed to MMC and analyzed by flow cytometry for the percentage of cells in the G2 phase of the cell cycle. FA is suspected when a large fraction of cells accumulate in G2. Determination of complementation groups. Based on somatic cell fusion studies, at least 15 complementation FA groups have been identified [A, B, C, D1 (BRCA2), D2, E, F, G, I, J (BRIP1/BACH1), L, M, N (PALB2), O (RAD51C), and P (SLX4). The FA complementation group can be identified by identifying which of the cDNA of the 15 FA-related genes, when expressed in the cells of the affected individual, corrects the DEB/MMC sensitivity phenotype [Pulsipher et al 1998]. Such testing is now possible [Chandra et al 2005].Laboratory findings that may be found in association with FA: Macrocytic red blood cells, often with increased fetal hemoglobin. These changes, which have no prognostic significance, often precede the onset of anemia. Normal or usually increased serum erythropoietin concentrationMolecular Genetic Testing Genes. Genes in which mutation is responsible for all of the 15 FA complementation groups have been identified: FANCA [Apostolou et al 1996, Fanconi Anaemia/Breast Cancer Consortium 1996, Lo Ten Foe et al 1996] FANCB [Meetei et al 2004] FANCC [Strathdee et al 1992] BRCA2 (FANCD1), which has been shown to be BRCA2 associated with hereditary breast and ovarian cancer in heterozygotes [Howlett et al 2002] FANCD2 [Timmers et al 2001] FANCE [de Winter et al 2000] FANCF [de Winter et al 2000] FANCG (XRCC9) [de Winter et al 2000] FANCI [Dorsman et al 2007, Sims et al 2007, Smogorzewska et al 2007] BRIP1(FANCJ or BACH1) [Levitus et al 2005, Levran et al 2005, Litman et al 2005] FANCL [Meetei et al 2003a] FANCM [Meetei et al 2005] PALB2 (FANCN) [Reid et al 2007, Xia et al 2007] RAD51C (FANCO) [Vaz et al 2010]SLX4 (FANCP) [Kim et al 2011, Stoepker et al 2011]Clinical testing Targeted mutation analysis for the common Ashkenazi Jewish FANCC mutation (c.456+4A>C; previously known as IVS4+4A>T)Sequence analysis for all the known genes associated with Fanconi anemia. Sequence analysis is complicated by the number of genes to be analyzed, the large number of possible mutations in each gene, the presence of large insertions or deletions in some genes, and the large size of many of the FA-related genes. If the complementation group has been established, the responsible mutation can be determined by sequencing the corresponding gene. Deletion/duplication analysis to detect deletions of one or more exons or of an entire geneTable 1. Summary of Molecular Genetic Testing Used in Fanconi AnemiaView in own windowComplementation GroupGene SymbolProportion of FA Attributable to Mutations in This Gene ^{1Test MethodMutations DetectedTest AvailabilityFA-AFANCA60%-70%Sequence analysisSequence variants 2Clinical Deletion/duplication analysis 3Exonic or whole-gene deletionsFA-BFANCB~2% Sequence analysisSequence variants 2Clinical Deletion/duplication analysis 3Exonic or whole-gene deletionsFA-CFANCC~14%Targeted mutation analysis c.456+4A>T, 67delG 4Clinical Sequence analysisSequence variants 2 including those in targeted analysisDeletion/duplication analysis 3Exonic or whole-gene deletionsFA-D1BRCA2~3% Sequence analysisSequence variants 2Clinical FA-D2FANCD2~3%Sequence analysisSequence variants 2Clinical FA-EFANCE~3%Sequence analysisSequence variants 2Clinical FA-FFANCF~2% Sequence analysisSequence variants 2Clinical FA-GFANCG~10%Sequence analysisSequence variants 2Clinical FA-IFANCI~1%Sequence analysisSequence variants 2Clinical FA-JBRIP1~2%Sequence analysisSequence variants 2Clinical FA-LFANCL~0.2%Sequence analysisSequence variants 2Clinical FA-M 5FANCM~0.2%Sequence analysisSequence variants 2Clinical FA-NPALB2~0.7%Sequence analysisSequence variants 2Clinical Deletion/duplication analysis 3Exonic or whole-gene deletionsFA-O 6RAD51C~0.2%Sequence analysisSequence variants 2Clinical FA-P 7SLX4~0.2%Sequence analysisSequence variants 2Clinical 1. Shimamura & Alter [2010]2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.4. Mutation panel may vary by laboratory.5. FA-M: Assignment of a formal complementation group for persons with FANCM mutations is still controversial since only one reference family/cell line has been identified and that cell line has been determined to have biallelic mutations in both FANCA and FANCM. Of note, under experimental conditions specific knockdown of FANCM alone results in an FA phenotype [Singh et al 2009].6. FA-O: Assignment of a formal complementation group for persons with RAD51C mutations is still controversial, as only one reference consanguineous family has been identified [Vaz et al 2010].7. FA-P: Assignment of a formal complementation group for persons with SLX4 mutations is still controversial as only a handful of reference families have been identified and SLX4 biology falls outside previously characterized FA proteins [Kim et al 2011, Stoepker et al 2011].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandPerform cytogenetic testing in blood for increased chromosomal breakage, rearrangements, and radials in the presence of diepoxybutane (DEB) or mitomycin C (MMC). Perform cytogenetic testing in the presence of diepoxybutane (DEB) or mitomycin C (MMC) in skin fibroblasts if blood is normal or inconclusive and mosaicism is suspected. Once cytogenetic testing has confirmed the diagnosis of FA, obtain complementation analysis (in a CLIA-certified laboratory) to identify the mutated gene [Chandra et al 2005], then obtain sequence analysis of the appropriate gene.
Note: Although some centers recommend sequencing of all genes without prior evaluation by complementation analysis [Ameziane et al 2008], this is prohibitively expensive at this time in the United States using conventional sequencing methods. Targeted mutation analysis of FANCC or sequencing of specific genes can be performed in ethnic groups in which there is a founder effect, as in the Ashkenazi Jewish mutation c.456+4A>T.Carrier testing for relatives at risk for the autosomal recessive forms of Fanconi anemia requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Carrier testing for relatives at risk for X-linked form of Fanconi anemia (FANCB mutations) requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are female heterozygotes for this X-linked disorder. (2) Identification of female carriers generally requires either (a) prior identification of the disease-causing mutation in the family or (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersHereditary breast and ovarian cancer is associated with heterozygous mutations in BRCA2 (FANCD1).Inherited monoallelic mutations in BRIP1 (also known as FANCJ) and PALB2 (also known as FANCN) have been implicated in breast cancer predisposition [Seal et al 2006, Rahman et al 2007].}

Natural HistoryThe primary clinical features of Fanconi anemia (FA) include physical abnormalities, progressive bone marrow failure manifest as pancytopenia, and cancer susceptibility; however, some individuals with FA have neither physical abnormalities nor bone marrow failure. Physical abnormalities. Physical anomalies are not generally a cause of mortality in individuals with Fanconi anemia. The likelihood of any physical abnormality is approximately 75%. The ratio of males to females is 1.2:1 (p <0.001 vs expected 1.00). The most commonly reported abnormalities and their frequency (see Note) include the following [Shimamura & Alter 2010]: Low birth weight (5%)Microsomia (40%). Short statureSkin (40%). Generalized hyperpigmentation; café au lait spots, hypopigmented areas SkeletalUpper limbs, unilateral or bilateral (35%) Thumbs (35%). Absent or hypoplastic, bifid, duplicated, rudimentary, attached by a thread, triphalangeal, long, low set Radii (7%). Absent or hypoplastic (only with abnormal thumbs), absent or weak pulse Hands (5%). Flat thenar eminence, absent first metacarpal, clinodactyly, polydactyly Ulnae (1%). Dysplastic, short Lower limbs (5%) Feet. Toe syndactyly, abnormal toes, club feet Legs. Congenital hip dislocation Neck (1%). Sprengel deformity, Klippel-Fiel anomaly, short, low hairline, webbed Spine (2%). Spina bifida, scoliosis, hemivertebrae, abnormal ribs, coccygeal aplasiaCraniofacialHead (20%). MicrocephalyFace (2%). Triangular, birdlike, dysmorphic, micrognathia, mid-face hypoplasiaEyes (20%). Small, cataracts, astigmatism; strabismus, epicanthal folds, hypotelorism, hypertelorism, ptosisRenal (20%). Kidneys: horseshoe, ectopic or pelvic, abnormal, hypoplastic or dysplastic, absent; hydronephrosis or hydroureter Gonads Males (25%). Hypospadias, micropenis; undescended testes, absent testes Females (2%). bicornuate uterus, malposition, small ovaries
Note: Fertility is reduced in males (albeit not entirely absent) due to hypo- or azospermia. Pregnancy is possible in females, whether or not they have undergone hematopoietic stem cell transplantation [Alter et al 1991, Dalle et al 2004].Developmental delay (10%). Intellectual disability, developmental delay Ears (10%). Hearing loss (usually conductive secondary to middle ear bony anomalies); abnormal shape (dysplastic, atretic, narrow ear canal [i.e., external auditory meatus], abnormal pinna)Cardiopulmonary (6%). Congenital heart defect: patent ductus arteriosus, atrial septal defect, ventricular septal defect, coarctation of the aorta, truncus arteriosus, situs inversus Gastrointestinal (5%). Esophageal, duodenal, jejunal atresia; imperforate anus; tracheoesophageal fistula; annular pancreas; malrotation of the gutCentral nervous system (3%). Small pituitary, pituitary stalk interruption syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus, dilated ventriclesNote: Percentages are calculated from 2000 cases reported in the literature from 1927 to 2009. Frequencies are approximate, since many reports did not mention physical descriptions. Bone marrow failure. The hematologic complications of FA typically occur within the first decade of life but are highly variable. Pancytopenia can present as early as the newborn period [Landmann et al 2004, Shimamura & Alter 2010]. Thrombocytopenia or leukopenia may precede anemia. Pancytopenia generally worsens over time. Neutropenia is associated with an increased risk for infections. Sweet syndrome (neutrophilic skin infiltration) has been reported in a few individuals with FA and myelodysplastic syndrome (MDS) [Baron et al 1989]. Severe bone marrow failure (defined as severe enough to lead to death or hematopoietic stem cell transplantation) has a peak hazard rate of about 5% per year at age ten years. In a competing risk analysis, the cumulative incidence of this complication as the first event is 55% by age 50 years [Rosenberg et al 2003, Alter et al 2010]; in a non-competing risk model, the cumulative risk of any hematologic finding (not necessarily severe) was 90% by age 50 years [Kutler et al 2003].Cancer susceptibility. In a review of individuals reported in the literature with FA, 9% developed leukemia (primarily acute myeloid leukemia [AML]) and 7% developed myelodysplastic syndrome (MDS) [Alter 2003a]. The relative risk for AML was increased approximately 500-fold in four different cohorts [Rosenberg et al 2003, Rosenberg et al 2008, Alter et al 2010, Tamary et al 2010]. In a competing risk analysis of the combined cohorts, the cumulative incidence of AML was 13% by age 50 years, with most cases between ages 15 and 35 years.The risk of developing solid tumors, particularly of the head and neck, skin, esophagus, and gynecologic area is also increased [Kutler et al 2003, Rosenberg et al 2003, Rosenberg et al 2008, Alter et al 2010, Tamary et al 2010]. The head and neck, esophageal, and vulvar tumors are squamous cell carcinomas. An increased incidence of human papillomavirus DNA reported in squamous cell carcinoma samples from individuals with FA in one cohort [Kutler et al 2003] was not confirmed in a separate report [van Zeeburg et al 2008]. The relative risk of solid tumors in the four cohorts was about 40-fold and the cumulative incidence 30% by age 50 years in a competing risk analysis.Individuals with FA receiving androgen treatment for bone marrow failure are at increased risk for liver tumors; however, two individuals out of about 45 with liver tumors had never received androgens. Malignancies are very difficult to treat (except surgically) because individuals with FA are sensitive to DNA-damaging agents such as chemotherapy and radiation.

Genotype-Phenotype CorrelationsFANCA. Among individuals with mutations in FANCA, those who are homozygous for null mutations (no protein production) may have earlier onset of anemia and higher incidence of leukemia than individuals with mutations that permit production of an abnormal FANCA protein [Faivre et al 2000]. FANCCThe FANCC c.456+4A>T mutation (also known as IVS4+4A>T), the most common FANCC mutation, is prevalent in individuals of Ashkenazi Jewish background. This mutation and the p.Arg548* and p.Leu554Pro mutations are associated with earlier onset of hematologic abnormalities and more birth defects than other mutations in FANCC, such as del22G. The p.Asp23Ilefs*23 and p.Gln13* mutations are associated with a lower risk of congenital abnormalities and later progression to bone marrow failure than the more severe mutations [Yamashita et al 1996, Gillio et al 1997]. Additional factors that appear to influence disease severity for a given FA genotype include the FANCC c.456+4A>T mutation which results in a milder phenotype in Japanese individuals than in Ashkenazi Jews [Futaki et al 2000]. BRCA2. Biallelic mutations in BRCA2 (also known as FANCD1) are associated with early-onset acute leukemia [Wagner et al 2004] and solid tumors [Hirsch et al 2004]. All persons with mutations in IVS7 developed AML by age three years; those with other BRCA2 mutations who developed AML did so by age six years [Alter 2006]. The cumulative probability of any malignancy was 97% by age six years, including AML, medulloblastomas, and Wilms tumor [Alter et al 2007]. FANCG. Mutations in FANCG may be associated with more severe cytopenia and a higher incidence of leukemia than other mutations; null mutations were in general more severe than mutations that produced an altered protein [Faivre et al 2000].

Differential DiagnosisFanconi anemia (FA) is the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.Cells derived from individuals with other chromosomal breakage syndromes, such as Bloom syndrome or ataxia-telangiectasia, may also exhibit high rates of spontaneous chromosomal breakage; however, only FA cells exhibit increased chromosomal breakage in response to DEB. Nijmegen breakage syndrome (NBS), characterized by short stature, progressive microcephaly with loss of cognitive skills, premature ovarian failure in females, recurrent sinopulmonary infections, and an increased risk for cancer, particularly lymphoma, may also manifest increased chromosomal breakage with MMC [Nakanishi et al 2002, Gennery et al 2004]. Inheritance is autosomal recessive. NBS may be distinguished from FA by DNA-based testing of NBS1, which detects mutations in almost 100% of individuals with NBS.Seckel syndrome, characterized by growth retardation, microcephaly with intellectual disability, and a characteristic 'bird-headed' facial appearance, may also show increased chromosome breakage with DNA cross-linking agents (MMC, DEB) [Andreassen et al 2004]. Some individuals with Seckel syndrome also develop pancytopenia and/or AML. Mutations in at least three genes are responsible for Seckel syndrome, only one of which (ATR) has been identified [O'Driscoll et al 2003]. Other disorders including neurofibromatosis 1 (which could be considered because of café au lait spots), TAR syndrome (thrombocytopenia with absent radii), and non-FA-related VACTERL association [Faivre et al 2005] (which could be considered because of radial ray defects) can be distinguished from FA by the DEB or MMC test.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementManagement focuses on surveillance and treatment of physical abnormalities, bone marrow failure, leukemia, and solid tumors. Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Fanconi anemia (FA), the following evaluations are recommended as needed:Physical abnormalities Ultrasound examination of the kidneys and urinary tract Formal hearing test Developmental assessment (particularly important for toddlers and school-age children) Referral to an ophthalmologist, otolaryngologist, endocrinologist, hand surgeon, gynecologist (for females as indicated), gastroenterologist, urologistEvaluation by a medical geneticist and genetic counseling Bone marrow failure Evaluation by a hematologist, to include complete blood count, fetal hemoglobin, and bone marrow aspirate for cell morphology and cytogenetics, as well as biopsy for cellularityHLA typing of the affected individual, sibs, and parents for consideration of hematopoietic stem cell transplantation Full blood typing Blood chemistries (assessing liver, kidney, and iron status) Treatment of ManifestationsRecommendations for treatment were agreed upon at a 2008 consensus conference [Eiler et al 2008; click for full text].Androgen administration. Androgens improve the blood counts in approximately 50% of individuals with FA. The earliest response is seen in red cells, with reticulocytosis and increase in hemoglobin generally occurring within the first month or two of treatment. Responses in the white cell count and platelet count are variable. Platelet responses are generally incomplete and may not be seen before several months of therapy. Such responses may be transient and improvement is generally greatest for the red cell count. Resistance to therapy may develop over time (generally years). The standard recommended androgen is oxymetholone at a starting dose of 2-5 mg/kg/day given orally. Androgen doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts. Side effects of androgen administration include liver toxicity such as elevated liver enzymes, cholestasis, peliosis hepatis (vascular lesion with multiple blood-filled cysts), and hepatic tumors [Shimamura & Alter 2010]. Hematopoietic growth factors. Granulocyte colony-stimulating factor (G-CSF), generally administered subcutaneously, improves the neutrophil count in some individuals. Note: A bone marrow aspirate and biopsy should be performed prior to the initiation of hematopoietic growth factor therapy and monitored regularly throughout treatment. Hematopoietic growth factors should be administered cautiously or not at all in the setting of a clonal cytogenetic bone marrow abnormality. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, including aplastic anemia, myelodysplastic syndrome, and acute leukemia. Donor stem cells may be obtained from bone marrow, peripheral blood (following stimulation of donor hematopoiesis with G-CSF), or cord blood. Ideally the HSCT is performed prior to onset of MDS/leukemia and before multiple transfusions are given for hematopoietic support [MacMillan & Wagner 2010]. HSCT should be performed at centers with expertise in HSCT for FA.Because individuals with FA are exquisitely sensitive to the toxicity of the usual chemotherapy and radiation regimens used in preparation for BMT, reduced doses are typically used. Graft failure, historically a major impediment to FA transplantation, has been largely ameliorated by use of fludaribine. Additionally, improvements in disease prophylaxis and treatment have led to greater use of alternative donors and decreased differences in the outcomes between sibling transplants and unrelated donor transplants. Individuals whose hematologic manifestations have been successfully treated with HSCT appear to be at an increased risk for solid tumors, particularly tongue squamous cell carcinomas. In one study the risk was increased fourfold and the median age of onset was 16 years younger than in persons with FA who were not transplanted [Rosenberg et al 2005]. Cancer treatment. Treatment of malignancies is challenging secondary to the increased toxicity associated with chemotherapy and radiation in FA. When possible, care should be obtained from centers experienced in the treatment of FA.Prevention of Secondary ComplicationsVaccination of females and males with the human papilloma virus vaccine (HPV) starting at age nine years is recommended in order to reduce the risk of gynecologic cancer in females (proven), and possibly reduce the risk of oral cancer in all individuals (not proven). SurveillancePhysical abnormalities. Growth and pubertal development must be monitored carefully and early referral to an endocrinologist should be made as indicated. Bone marrow failure. General recommendations vary. Regular blood counts, every two to three months while stable, more often as needed. Bone marrow aspirate/biopsy recommended at least annually to evaluate morphology, cellularity (from the biopsy), and cytogenetics (the latter for emergence of a malignant clone). Recommendations for monitoring of blood and bone marrow parameters were agreed upon at a 2008 consensus conference [Eiler et al 2008; click for full text].Androgen administration. For individuals receiving androgen therapy: Monitoring of liver chemistry profile Ultrasound examination of the liver every six to 12 months for androgen-related changes, including tumors.Cancer surveillance. The majority of solid tumors develop after the first or second decade of life. Prompt and aggressive workup for any symptoms suggestive of a malignancy should be pursued. Detection and surgical removal of early-stage cancers remains the mainstay of therapy. Surveillance regimens should include the following:Annual gynecologic examination and Pap smears, beginning at menarche or age16 years, whichever is firstFrequent dental and oropharyngeal examinations, including nasolaryngoscopy starting at age ten years, or within the first year after HSCTAnnual esophageal endoscopy may be considered, but there are no guidelines, and currently most centers require anesthesia for this procedure. Agents/Circumstances to AvoidBlood transfusions. Transfusions of red cells or platelets should be avoided or minimized for individuals who are candidates for HSCT. To reduce the chances of sensitization, family members must not act as blood donors if HSCT is being considered.All blood products should be filtered (leukodepleted) and irradiated. Cancer prevention. Given the increased susceptibility of individuals with FA to developing leukemias and other malignancies, affected individuals are advised to avoid toxic agents including smoking, second-hand smoke, and alcohol, which have been implicated in tumorigenesis.Due to the sensitivity of individuals with FA to radiation, radiographic studies for the purpose of surveillance should be minimized in the absence of clinical indications. However, baseline skeletal surveys may be considered, in order to document bony anomalies that may lead to problems with age, such as anomalies of the wrist, hip, and vertebrae. Evaluation of Relatives at RiskIt is appropriate to perform DEB/MMC testing or molecular genetic testing (if the family specific mutations are known) on all sibs of an affected individual for early diagnosis and appropriate monitoring for physical abnormalities, bone marrow failure, and related cancers.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Pregnancy is possible in females with FA, whether or not they have undergone hematopoietic stem cell transplantation [Alter et al 1991, Dalle et al 2004]. Pregnancy needs to be managed by a high-risk maternal fetal obstetrician along with a hematologist. Therapies Under InvestigationGene therapy, a theoretic possibility, is at a research stage only. Theoretically FA is an ideal disease for gene therapy, because the cells would gain a growth advantage by acquisition of a normal (wild type) allele. However, gene therapy used in hematopoietic cells would not reduce the risk of solid tumors in other tissues. Early phase trials of gene therapy for individuals with mutations in FANCC described transient retroviral FANCC transduction in hematopoietic cells [Liu et al 1999]. Because previous clinical trials failed to accomplish permanent gene correction of stem cells, current work is focusing on development of novel vector and delivery strategies.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Fanconi Anemia: Genes and DatabasesView in own windowComplementation GroupGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFA-CFANCC9q22​.32Fanconi anemia group C proteinFanconi Anemia Mutation Database (FANCC)FANCCFA-AFANCA16q24​.3Fanconi anemia group A proteinFanconi Anemia Mutation Database (FANCA)FANCAFA-BFANCBXp22​.2Fanconi anemia group B proteinFANCB @ LOVD
Fanconi Anaemia Mutation Database (FANCB)FANCBFA-D2FANCD23p25​.3Fanconi anemia group D2 proteinFanconi Anaemia Mutation Database (FANCD2)FANCD2FA-EFANCE6p21​.31Fanconi anemia group E proteinFanconi Anaemia Mutation Database (FANCE)FANCEFA-FFANCF11p14​.3Fanconi anemia group F proteinFanconi Anaemia Mutation Database (FANCF)FANCFFA-GFANCG9p13​.3Fanconi anemia group G proteinFanconi Anaemia Mutation Database (FANCG)FANCGFA-D1BRCA213q13​.1Breast cancer type 2 susceptibility proteinCatalogue of Somatic Mutations in Cancer (COSMIC)
BRCA2 @ ZAC-GGM
Fanconi Anaemia Mutation Database (FANCD1 - BRCA2)
Breast Cancer Information Core (BIC)
BRCA2 homepage - LOVDBRCA2FA-JBRIP117q23​.2Fanconi anemia group J proteinFanconi Anaemia Mutation Database (FANCJ - BRIP1)
BRIP1 @ LOVDBRIP1FA-LFANCL2p16​.1E3 ubiquitin-protein ligase FANCLFanconi Anaemia Mutation Database (FANCL)FANCLFA-IFANCI15q26​.1Fanconi anemia group I proteinFanconi Anemia Mutation Database (FANCI)FANCIFA-NPALB216p12​.2Partner and localizer of BRCA2Fanconi Anaemia Mutation Database (FANCN - PALB2)
PALB2 @ LOVDPALB2FA-MFANCM14q21​.2Fanconi anemia group M proteinFanconi Anaemia Mutation Database (FANCM)FANCMFA-ORAD51C17q22DNA repair protein RAD51 homolog 3RAD51C @ LOVDRAD51CFA-PSLX416p13​.3Structure-specific endonuclease subunit SLX4SLX4 @ LOVDSLX4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Fanconi Anemia (View All in OMIM) View in own window 227645FANCONI ANEMIA, COMPLEMENTATION GROUP C; FANCC 227646FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2 227650FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA 300514FANCONI ANEMIA, COMPLEMENTATION GROUP B; FANCB 300515FANCB GENE; FANCB 600185BRCA2 GENE; BRCA2 600901FANCONI ANEMIA, COMPLEMENTATION GROUP E; FANCE 602774RAD51, S. CEREVISIAE, HOMOLOG OF, C; RAD51C 602956FANCG GENE; FANCG 603467FANCONI ANEMIA, COMPLEMENTATION GROUP F; FANCF 605724FANCONI ANEMIA, COMPLEMENTATION GROUP D1; FANCD1 605882BRCA1-INTERACTING PROTEIN 1; BRIP1 607139FANCA GENE; FANCA 608111FANCL GENE; FANCL 609053FANCONI ANEMIA, COMPLEMENTATION GROUP I; FANCI 609054FANCONI ANEMIA, COMPLEMENTATION GROUP J; FANCJ 609644FANCM GENE; FANCM 610355PARTNER AND LOCALIZER OF BRCA2; PALB2 610832FANCONI ANEMIA, COMPLEMENTATION GROUP N; FANCN 611360FANCI GENE; FANCI 613278SLX4, S. CEREVISIAE, HOMOLOG OF; SLX4 613390FANCONI ANEMIA, COMPLEMENTATION GROUP O; FANCO 613897FANCF GENE; FANCF 613899FANCC GENE; FANCC 613951FANCONI ANEMIA, COMPLEMENTATION GROUP P; FANCP 613976FANCE GENE; FANCE 613984FANCD2 GENE; FANCD2 614082FANCONI ANEMIA, COMPLEMENTATION GROUP G; FANCG 614083FANCONI ANEMIA, COMPLEMENTATION GROUP L; FANCL 614087FANCONI ANEMIA, COMPLEMENTATION GROUP M; FANCMNote: The detailed discussion of protein interactions and signaling described in this section and Figure 1 has been simplified by replacing the long names of the proteins with their non-italicized gene acronym (e.g., FANCA instead of Fanconi anemia group A protein; BRCA2 instead of breast cancer type 2 susceptibility protein). See Table A for gene and protein names.FigureFigure 1. Current model of the Fanconi anemia pathway. Eight FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with FAAP100 and FAAP24 form a nuclear protein complex (the FA core complex) with E3 ubiquitin ligase activity. (more...)Molecular Genetic PathogenesisThirteen genes that are involved in Fanconi anemia (FA) and also account for each of the 13 phenotypic complementation groups, have been identified. The FA-M group has been further refined to be complex in that the only reference cell line is actually a double FANCA and FANCM mutant, clouding the notion that FANCM is a bona fide FA-related gene [Singh et al 2009]. The proteins encoded by the FA-related genes are considered to work together in a common pathway/network called "the FA pathway" or "the FA-BRCA pathway/network," which regulates cellular resistance to DNA cross-linking agents [Taniguchi & D'Andrea 2006]. Disruption of this pathway leads to the common cellular and clinical abnormalities observed in FA [Garcia-Higuera et al 2001].Eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM), along with proteins FAAP24 [Ciccia et al 2007] and FAAP100 [Ling et al 2007] are assembled in a nuclear complex (FA core complex). This complex is a multi-subunit ubiquitin ligase complex; monoubiquitination of two FA proteins (FANCD2 and FANCI) depends on the FA core complex [Garcia-Higuera et al 2001, Smogorzewska et al 2007]. In response to DNA damage or in S phase of the cell cycle, this FA core complex activates the monoubiquitination of the FANCD2 and FANCI proteins. Monoubiquitinated FANCD2 and monoubiquitinated FANCI are translocated to nuclear foci containing the proteins BRCA1, BRCA2, PALB2, and RAD51. FANCI shares sequence similarity with FANCD2; together they form a protein complex (ID complex) [Smogorzewska et al 2007]. Monoubiquitination of FANCD2 and FANCI depend on each other [Smogorzewska et al 2007]. A nuclease, FAN1, has been shown to bind to monoubiquitylated FANCD2, which directs its enzymatic activity [Huang & D'Andrea 2010]. A cell-free system has been used to recapitulate cross-link repair in vitro [Knipscheer et al 2009].One of the components of the FA core complex, FANCL, has a PHD (plant homeodomain) finger (a variant RING finger) domain with ubiquitin ligase activity [Meetei et al 2003a]. FANCL associates through its PHD/RING finger domain with UBE2T, a ubiquitin conjugating enzyme (E2), which is also required for FANCD2 monoubiquitination [Machida et al 2006]. Recombinant FANCL, the E2 UBE2T, FANCD2, FANCI, and FANCE recapitulate the monoubiquitination reaction in vitro [Alpi et al 2008].Another component of the FA core complex, FANCM, is homologous to the archaeal DNA helicase/nuclease known as HEF. FANCM has DNA helicase motifs and a degenerate nuclease motif and exhibits DNA-stimulated ATPase activity and DNA translocase activity [Meetei et al 2005]. A FANCM-interacting protein, FAAP24, preferentially binds to single-stranded DNA and branched DNA structures [Ciccia et al 2007]. Therefore, it has been speculated that FANCM DNA translocase activity could play an important role in displacing the FA core complex along the DNA, allowing DNA damage recognition, or that FAAP24 may play a role in targeting the FA core complex to abnormal, branched DNA structures. This complex is thought to be responsible for a replication-associated checkpoint response involving RPA [Huang et al 2010] and the BLM helicase [Deans & West 2009]. As is true for multiple FA proteins, the complex appears to be regulated through ATR [Collis et al 2008].Furthermore, the FA core complex forms a larger complex with BLM, RPA, and topoisomerase IIIα, called BRAFT (BLM, RPA, FA, and topoisomerase IIIα) [Meetei et al 2003b] in a further link to Bloom syndrome. FANCM is found in both separable complexes: the FA core complex as well as the BLM complex [Deans & West 2009].A DNA damage-activated signaling kinase, ATR, a single-strand DNA-binding protein complex, RPA, and an ATR-associated protein, HCLK2, are required for DNA damage-inducible monoubiquitnation and foci formation of FANCD2 [Andreassen et al 2004, Collis et al 2007]. BRCA1 [Garcia-Higuera et al 2001, Vandenberg et al 2003] and histone H2AX [Bogliolo et al 2007] are required for DNA damage-inducible foci formation of FANCD2, but not for monoubiquitination of FANCD2. These factors are considered to be upstream positive regulators of the FA pathway. ATR has been shown to directly phosphorylate FANCA and indirectly phosphorylate FANCD2 through CHK1 [Zhi et al 2009]. As described, ATR is also necessary for assembly of FANCM and recruitment of RPA at the ICL-induced checkpoint [Collis et al 2008].BRCA2 (previously known as FANCD1) is a tumor suppressor that confers breast cancer susceptibility [Howlett et al 2002]. BRCA2 protein stability and localization is regulated by PALB2 (partner and localizer of BRCA2) [Xia et al 2006]. PALB2, another breast cancer susceptibility gene [Rahman et al 2007], is responsible for FA complementation group FA-N and the gene sometimes called FANCN [Reid et al 2007, Xia et al 2007]. Another breast cancer susceptibility gene [Seal et al 2006], BRIP1 (originally known as BACH1 for BRCA1-associated C-terminal helicase 1) [Cantor et al 2001], is also an FA-related gene and is the basis for complementation group FA-J [Levitus et al 2005, Levran et al 2005, Litman et al 2005]. BRCA2, PALB2, and BRIP1 are not required for FANCD2 protein monoubiquitination or FANCD2 nuclear foci formation, but are still required for cellular resistance to MMC or DEB. BRCA2 has been found to act in multiple subcomplexes of FA proteins, including FANCG and FANCD2 [Wilson et al 2010], suggesting that the notion of acting downstream of FANCD2 monoubiquitination may be too simplistic. Phosphorylation of FANCD2 by CHK1 has been shown to be necessary for interaction with BRCA2 [Zhi et al 2009]. FANCJ and FANCD2 have also been shown to be functionally linked in foci formation [Zhang et al 2010].USP1 is a deubiquitinating enzyme that removes ubiquitin from monoubiquitinated FANCD2, and negatively regulates the FA pathway along with its coactivator UAF1 [Nijman et al 2005, Cohn et al 2007]. USP1 also removes ubiquitin from monoubiquitylated PCNA (proliferating cell nuclear antigen) [Huang et al 2006]. This may not be coincidental, since FANCD2 and PCNA have been shown to bind [Howlett et al 2009]. The deubiquitination event has been shown to be vital for FA function [Oestergaard et al 2007]. Hematopoeitic defects have been noted in knockout mice [Parmar et al 2010].In nuclear foci, FANCD2 colocalizes with FANCI, BRCA1, BRCA2, PALB2, RAD51, BLM, RPA, ATR, FANCC, and FANCE [Garcia-Higuera et al 2001, Pace et al 2002, Taniguchi et al 2002a, Andreassen et al 2004, Wang et al 2004, Matsushita et al 2005, Xia et al 2006, Smogorzewska et al 2007]. FANCD2 also colocalizes partially with BRIP1 [Litman et al 2005] and NBS1 [Nakanishi et al 2002]. All of these factors are required for cellular resistance to DNA cross-linking agents and are considered to work together to repair interstrand DNA cross-links, although the precise mechanism is not understood. Recently, mutations in RAD51C have been detected in several FA-like cases in a consanguineous family, also associated with breast and ovarian cancer susceptibility [Meindl et al 2010, Vaz et al 2010].Among FA proteins, BRCA2 has a clear role in regulating homologous recombination by controlling the activity of RAD51, the eukaryotic homolog of bacterial RecA [Davies et al 2001, Moynahan et al 2001]. PALB2 regulates BRCA2 stability and localization in nuclear structures (chromatin and nuclear matrix) and, thus, is required for homologous recombination [Xia et al 2006]. The FA core complex, FANCD2, FANCI [Smogorzewska et al 2007], and FANCJ [Litman et al 2005] are also reported to be required for efficient homologous recombination, although conflicting reports exist [Taniguchi & D'Andrea 2006].FANCD2 protein is also phosphorylated by the ataxia-telangiectasia kinase, ATM, in a process that regulates a radiation-induced S phase checkpoint [Taniguchi et al 2002b, Ho et al 2006]. While required for resistance to ionizing radiation, this phosphorylation event is dispensable for cross-linker resistance, implying a separation of or dual function for FANCD2. FANCD2 appears to be phosphorylated by CHK1, which is downstream of ATR, at serine 331 in a manner that results in activation by cross-links [Zhi et al 2009].Importantly, a number of studies have shown defects in the FA-BRCA pathway to be implicated in cancer:Individuals with FA are susceptible to both leukemia and solid tumors [Alter 2003b]. Fancd2, Fanca, or Fancc knockout mice develop tumors [Houghtaling et al 2003, Wong et al 2003, Carreau 2004]. Inactivation of the FA pathway by methylation of FANCF has been found in a wide variety of human cancers (ovarian, breast, non-small cell lung, cervical, testicular, and head and neck squamous cell cancers) in the general population (non-FA individuals) [Olopade & Wei 2003, Taniguchi et al 2003, Marsit et al 2004, Narayan et al 2004, Wang et al 2006]. Inherited and somatic mutations of FANCC and FANCG are present in a subset of young-onset pancreatic cancers [van Der Heijden et al 2003]. BRCA1 and BRCA2 are well-known tumor suppressor genes responsible for familial breast/ovarian cancer [Turner et al 2004]. Truncating mutations in the FA-related genes BRIP1 and PALB2 are breast cancer susceptibility alleles [Seal et al 2006, Erkko et al 2007, Rahman et al 2007, Tischkowitz et al 2007]. These findings underscore the importance of the FA-BRCA pathway in tumor suppression. Because the FA pathway is required for cellular resistance to interstrand DNA cross-linking agents (e.g., cisplatin, MMC, melphalan), tumors with defects in the FA pathway are expected to be hypersensitive to these widely used anti-cancer agents. Therefore, the FA-BRCA pathway is an attractive target for developing small molecule inhibitors that may be useful as chemosensitizers [Chirnomas et al 2006].Other manipulators of the FA pathway include curcumin, which has been demonstrated to inhibit the FA pathway and, thus, increase the sensitivity of tumors to cisplatin [Chirnomas et al 2006]. Another avenue of recent excitement has been the use of poly adenosine diphosphate ribose polymerase inhibitors, which target alternative pathways of homologous recombination repair and again enable better response to cross-linkers [Martin et al 2010]. Anti-oxidative agents have been shown to delay the onset of tumors in mouse models of FA [Zhang et al 2008].Amelioration of FA pathology has been implicated in reports of downregulation of elements of the non-homologous end joining pathway [Adamo et al 2010]. These data propose that much of FA pathophysiology results from the unfettered work of NHEJ promoting inaccurate repair. On the other hand, FA involvement in homologous recombinatorial repair has been well established in interactions with BRCA1, BRCA2, and RAD51C. FANCD2 has also been shown to interact with PCNA and pol K, suggesting that translesion synthesis, a variant of HR, may be the most direct function of FA proteins in bypass of the lesion as an intermediate to HRR [Ho & Schärer 2010, Song et al 2010].For reviews of the molecular biology of FA, see D'Andrea & Grompe [2003], Venkitaraman [2004], Collins & Kupfer [2005], Kennedy & D'Andrea [2005], Niedernhofer et al [2005], Bagby & Alter [2006], Gurtan & D'Andrea [2006], Lyakhovich & Surralles [2006], Mathew [2006], Mirchandani & D'Andrea [2006], Taniguchi & D'Andrea [2006], Green & Kupfer [2009], and Thompson & Hinz [2009].FANCA Normal allelic variants. FANCA has two isoforms. Reference sequence NM_000135.2 has 43 exons and encodes the longer isoform. Pathologic allelic variants. The pathologic alleles of FANCA are numerous and highly variable among families [Levran et al 1997, Morgan et al 1999, Wijker et al 1999]. A small percentage of families share the mutations p.Phe1263del and p.Val372AlafsX42, the latter of which is found in affected individuals of northern European ancestry. See Table A. Table 2. Selected FANCA Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1115_1118delp.Val372AlafsX42NM_000135​.2
NP_000126​.2c.3788_3790delp.Phe1263delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. FANCA encoded by the longer isoform has 1455 amino acids (reference sequence NM_000126). FANCA is a component of the FA core complex. FANCA contains two overlapping bipartite nuclear localization signals (NLS), five functional leucine-rich nuclear export sequences (NESs) and a partial leucine zipper sequence [Fanconi Anaemia/Breast Cancer Consortium 1996, Lo Ten Foe et al 1996, Ferrer et al 2005]. The nuclear export of FANCA is regulated in a CRM1-dependent manner [Ferrer et al 2005]. FANCA is a phosphoprotein. FANCA is a client of Hsp90 [Oda et al 2007]. Recent reports suggest that FANCA is phosphorylated by the ATR kinase at serine 1449 [Collins et al 2009].Abnormal gene product. See Molecular Genetic Pathogenesis. FANCB Normal allelic variants. FANCB has ten exons with the translation start in exon 3 (reference sequence NM_001018113.1). FAAP95 is an alias for FANCB. Pathologic allelic variants. See Table A. Normal gene product. FANCB comprises 853 amino acids; some sequences have 859 residues, depending on the initiating methionine. FANCB is a component of the FA core complex and contains a putative bipartite NLS [Meetei et al 2004]. Abnormal gene product. See Molecular Genetic Pathogenesis. FANCC Normal allelic variants. FANCC has 15 exons (reference sequence NM_000136.2). Pathologic allelic variants. Three common mutations in FANCC have been identified (c.456+4A>T, p.Arg548X, and c.67delG) [Whitney et al 1993], as well as several rare mutations (p.Gln13X, p.Arg185X, and p.Leu554Pro). The mutation c.456+4A>T has been found primarily in the Ashkenazi Jewish population; recently, it has also been reported in a Japanese cohort. The mutations p.Arg548X, c.67delG, p.Arg185X, and p.Leu554Pro are prevalent in individuals of northern European ancestry. The mutation p.Gln13X is found in individuals from southern Italy. See Table A. Table 3. Selected FANCC Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.456+4A>T
(IVS4+4A>T)--NM_000136​.2
NP_000127​.2c.37C>Tp.Gln13Xc.67delG
(322delG)p.Asp23IlefsX23c.553C>Tp.Arg185Xc.1642C>Tp.Arg548Xc.1661T>Cp.Leu554ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. FANCC has 558 amino acids. It is a component of the FA core complex, but localizes both to both the nucleus and the cytoplasm [Yamashita et al 1994]. Some functions of FANCC outside of the FA core complex have been also proposed [Fagerlie et al 2004]. Reports suggest that STAT1 binds to FANCC to modulate JAK-STAT signaling and to protect cells from interferon gamma toxic effects [Pang et al 2000, Fagerlie et al 2004].Abnormal gene product. See Molecular Genetic Pathogenesis. BRCA2 Normal allelic variants. BRCA2, also known as FANCD1, has 27 exons (reference sequence NM_000059.3). Pathologic allelic variants. See Table A. Normal gene product. The breast cancer type 2 susceptibility protein (BRCA2) has 3418 amino acids. BRCA2 regulates homologous recombination repair through control of RAD51 recombinase (eukaryotic homologue of bacterial RecA) [Davies et al 2001, Moynahan et al 2001]. BRCA2 also has other functions including stabilization of stalled replication forks and regulation of cytokinesis [Daniels et al 2004]. BRCA2 has been demonstrated to work in concert with RAD51 to orchestrate the repair of double strand break ends, prompting the nucleation of each end by RAD51. BRCA2 has been found in various subcomplexes with other FA proteins, including FANCG, FANCD2, and PALB2 [Xia et al 2007, Wilson et al 2010].Abnormal gene product. See Molecular Genetic Pathogenesis. FANCD2 Normal allelic variants. FANCD2 has two isoforms. Isoform a (reference sequence NM_033084.3) has 43 exons. Isoform b (reference sequence NM_001018115.1) has 44 exons and an alternate 3' coding sequence resulting in a shorter and distinct C-terminus. FANCD2 protein encoded by isoform b (exon 44 form) is the functional FANCD2, and the protein encoded by isoform a (exon 43 form) is not functional [Montes de Oca et al 2005]. Pathologic allelic variants. See Table A. Normal gene product. FANCD2 has 1451 amino acids (isoform b) and shares sequence similarity with FANCI. FANCD2 and FANCI form a protein complex (ID complex). FANCD2 can be monoubiquitinated on lysine 561 in an FA core complex-, UBE2T-, and FANCI-dependent manner. Monoubiquitinated FANCD2 is translocated to chromatin fraction, and form nuclear foci with FANCI, BRCA1, BRCA2, RAD51, etc. FANCD2 can be phosphorylated by ATM [Taniguchi et al 2002b, Ho et al 2006] and possibly by ATR [Andreassen et al 2004, Pichierri & Rosselli 2004] in response to DNA damage. A recent report suggests that FANCD2 is phosphorylated at serine 331 by CHK1 in a manner that is required for binding to BRCA2 [Zhi et al 2009]. Important studies have shown FANCD2 to have a function in resection of ends surrounding a cross-link in the repair process [Knipscheer et al 2009]. A nuclease, FAN1, has been demonstrated to bind to FANCD2 [Huang & D'Andrea 2010].Abnormal gene product. See Molecular Genetic Pathogenesis. FANCE Normal allelic variants. FANCE has 14 exons (reference sequence NM_021922.2). Pathologic allelic variants. See Table A. Normal gene product. FANCE has 536 amino acids and is a component of the FA core complex. FANCE directly binds to FANCD2. FANCE contains two nuclear localization signals (NLS). FANCE has five tandem repeats of a short helical motif (FANC repeats) [Nookala et al 2007]. It purportedly has function as a shuttle protein between the FA core complex and FANCD2 in a fashion dependent on phosphorylation [Wang et al 2007]. Abnormal gene product. See Molecular Genetic Pathogenesis. FANCF Normal allelic variants. FANCF has a single exon (reference sequence NM_022725.2). Pathologic allelic variants. See Table A. Normal gene product. FANCF has 374 amino acids and is a component of the FA core complex. FANCF acts as a flexible adaptor protein required for the assembly of the FA core complex [Léveillé et al 2004]. Crystallographic studies of the C-terminal domain revealed a helical repeat structure similar to the Cand1 regulator of the Cul1-Rbx1-Skp1-Fbox(Skp2) ubiquitin ligase complex [Kowal et al 2007]. Abnormal gene product. See Molecular Genetic Pathogenesis. FANCG Normal allelic variants. FANCG has 14 exons (reference sequence NM_004629.1). Pathologic allelic variants. The mutations in FANCG are highly variable, but more common variant alleles have been described in specific populations: c.307+1G>C (Korean/Japanese); c.925-2A>G (Brazilian); c.1480+1G>C (French Canadian); p.Gly395TrpfsX5 (northern European); and p.Trp599ProfsX49 (northern European) [Demuth et al 2000, Nakanishi et al 2002]. See Table A. Table 4. Selected FANCG Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.307+1G>C
(IVS3+1G>C)--NM_004629​.1
NP_004620​.1c.925-2A>G
(IVS8-2A>G)--c.1183-1192del
(1184-1194del)p.Glu395TrpfsX5c.1480+1G>C
(IVS11+1G>C)p.Trp599ProfsX49c.1794_1803delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. FANCG has 622 amino acids. It is a component of the FA core complex. FANCG has seven tetratricopeptide repeat motifs (TPRs) [Blom et al 2004]. FANCG is a phosphoprotein; serines 383 and 387 on FANCG are phosphorylated in M phase, presumably by cdc2 [Mi et al 2004]. These two sites are important for exclusion of FANCG from chromatin in mitosis. Phosphorylation of serine 7 of FANCG is upregulated after MMC treatment [Qiao et al 2004]. FANCA and FANCG stabilize each other. Recent data have demonstrated FANCG, FANCD1/BRCA2, FANCD2, and XRCC3 participate in the same protein complex. This implies multifunctionality of FANCG by its presence in the core complex as well as in homologous recombinatorial repair [Wang et al 2007]. Abnormal gene product. See Molecular Genetic Pathogenesis. FANCI Normal allelic variants. FANCI has 37 exons (reference sequence NM_018193.2). Pathologic allelic variants. See Table A.Normal gene product. FANCI has 1268 amino acids and shares sequence similarity with FANCD2. FANCD2 and FANCI form a protein complex (ID complex). FANCI can be monoubiquitinated on lysine 523 in an FA core complex-, UBE2T-, and FANCD2-dependent manner. Monoubiquitinated FANCI is translocated to nuclear foci and colocalizes with BRCA1, BRCA2, RAD51, FANCD2, etc. FANCI is a phosphoprotein. DNA damage-induced phosphorylation of p.Ser730, p.Thr952, and p.Ser1121 of human FANCI can be detected [Smogorzewska et al 2007]. FANCI functions in an analogous manner as FANCD2 and can be analyzed in the same fashion in assays including DNA repair foci, cell survival, and monoubiquitylation [Ishiai et al 2008].Abnormal gene product. See Molecular Genetic Pathogenesis. BRIP1 Normal allelic variants. BRIP1 (BRCA1 interacting protein C-terminal helicase 1) has 20 exons. This gene has also been called FANCJ or BACH1. Pathologic allelic variants. See Table A. Normal gene product. The Fanconi anemia group J protein (BRIP1 or FANCJ) has 1249 amino acids and is a DNA-dependent ATPase and a 5'-to-3' DNA helicase (DEAH helicase) that binds directly to the BRCT domain of BRCA1 [Cantor et al 2001]. FANCJ contains the seven helicase-specific motifs and C-terminal extension, which has 39% homology with synaptonemal complex protein 1, a major component of the transverse filaments of developing meiotic chromosomes [Cantor et al 2001]. FANCJ helicase domain clearly is important for FA pathway function [Wu & Brosh 2009]. FANCJ also appears to interdigitate with the mismatch repair pathway in binding to MLH1 [Cantor & Xie 2010].Abnormal gene product. See Molecular Genetic Pathogenesis. FANCL Normal allelic variants. FANCL has 14 exons (reference sequence NM_018062.2). Pathologic allelic variants. See Table A. Normal gene product. The E3 ubiquitin-protein ligase FANCL has 375 amino acids. It is a component of the FA core complex with three WD40 (Tryptophan-Aspartate -40) repeats and a PHD finger motif (a variant RING finger motif) [Meetei et al 2003a] and is presumed to be the catalytic subunit of the FA core complex as an ubiquitin ligase for FANCD2 and FANCI. FANCL directly interact with UBE2T (E2 ubiquitin conjugating enzyme) [Machida et al 2006]. A baculoviral generated protein has been shown to have in vitro monoubiquitylation activity [Alpi et al 2008].Abnormal gene product. See Molecular Genetic Pathogenesis. FANCM Normal allelic variants. FANCM has 23 exons (reference sequence NM_020937.1). Pathologic allelic variants. See Table A. Normal gene product. The Fanconi anemia group M protein (FANCM) has 2048 animo acids. It is a component of the FA core complex, contains the seven helicase-specific motifs, one degenerate endonuclease domain, and ssDNA and dsDNA-stimulated ATPase activity and DNA translocase activity [Meetei et al 2005]. FANCM is phosphorylated in response to DNA damage. In concert with FAAP24, a FANCM binding protein, FANCM participates in a checkpoint reaction to DNA damage [Huang et al 2010].Abnormal gene product. See Molecular Genetic Pathogenesis. PALB2 Normal allelic variants. PALB2 (also known as FANCN) has 13 exons (reference sequence NM_024675.3). Pathologic allelic variants. See Table A. Normal gene product. The partner and localizer of BRCA2 protein (PALB2) has 1186 amino acids. It regulates localization and stability of BRCA2 protein. Short sections of the PALB2 N-terminus share homologies with a segment of prefoldin and the light chain 3 (LC3) of microtubule-associated protein MAP1. PALB2 also has two WD40 repeat-like segments at the C terminus [Xia et al 2006]. PALB2 is one of the FA-related genes that is also a breast cancer susceptibility gene. It is a known protein partner of FANCD1/BRCA2 and plays a role in the homologous recombination repair pathway [Xia et al 2007].Abnormal gene product. See Molecular Genetic Pathogenesis. RAD51C (FANCO)Normal allelic variants. RAD51C has 9 exons (reference sequence NM_058216).Pathologic allelic variants. See Table A. Normal gene product. RAD51C is a protein of 376 amino acids shown to participate in several distinct protein complexes involved in homologous recombination. RAD51 variants have been demonstrated to bind to single strand overhangs that occur after processing of DNA lesions in concert with BRCA2 [Somyajit et al 2010].Abnormal gene product. See Molecular Genetic Pathogenesis. SLX4 (FANCP)Normal allelic variants. SLX4 has 15 exons (reference sequence NM_032444).Pathologic allelic variants. See Table A. Normal gene product. SLX4 is a protein of 1834 amino acids that appears to be involved in resolution of homologous recombination intermediates, such as Holliday junctions. SLX4 appears to interact with other endonuclease complexes, including MUS81-EME1 and XPF-ERCC1 [Kim et al 2011, Stoepker et al 2011].Abnormal gene product. See Molecular Genetic Pathogenesis.