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| Confirmed Fanconi anaemia or Bloom syndrome v2.8 | RAD51C |
Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018 Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth. Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis. PMID: 26681308 Ameziane et al., 2015 Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs. PMID: 26253028 Wang et al., 2015 1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C. PMID: 20400963 Vaz et al., 2010 Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C. Functional evidence: PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice. This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018 Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth. Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis. PMID: 26681308 Ameziane et al., 2015 Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs. PMID: 26253028 Wang et al., 2015 1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C. PMID: 20400963 Vaz et al., 2010 Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C. Functional evidence: PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice. This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023. |
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| Confirmed Fanconi anaemia or Bloom syndrome v2.7 | RAD51C |
Ida Ertmanska changed review comment from: PMID: 29278735 Jacquinet et al., 2018 Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth. Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis. PMID: 26681308 Ameziane et al., 2015 Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs. PMID: 26253028 Wang et al., 2015 1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C. PMID: 20400963 Vaz et al., 2010 Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C. This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023.; to: PMID: 29278735 Jacquinet et al., 2018 Report of a newborn female with an expanded phenotype of Fanconi anemia, complementation group O (FANCO). Prenatal trio exome seq detected compound heterozygous variants in RAD51C NM_058216.2: c.935G>A (p.Arg312Gln) and c.571+5G>A. Diagnosed prenatally with several congenital anomalies. Chromosome breakage studies confirmed the diagnosis of FANCO, with expanded phenotype of cleft lip and palate and lobar holoprosencephaly. The patient died shortly after birth. Functional: PMID: 37031326 Zemet et al., 2023 - trio WGS studies in the same family as PMID: 29278735 revealed SNV hypermutagenesis. PMID: 26681308 Ameziane et al., 2015 Report of a de novo heterozygous RAD51C variant g.41022153G>A; p.Ala293Thr (NM_002875). The atypical FA-like individual presented at 2.5 years of age with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle. A positive DNA cross-linker (DEB)-induced chromosomal breakage test confirmed the suspicion of FA. Lack of typical bone marrow failure and malignancies at age 23yrs. PMID: 26253028 Wang et al., 2015 1yo girl born with radial dysplasia, absent right thumb, pelvic left kidney and increased DNA damage sensitivity, including the appearance of radial chromosomes in peripheral blood lymphoblasts and skin fibroblasts after treatment with diepoxybutane (DEB) and mitomycin C (MMC); diagnosed with Fanconi Anemia. WES revealed a de novo heterozygous mutation in RAD51: c.391A>C. PMID: 20400963 Vaz et al., 2010 Consanguineous Pakistani family; 3 siblings with extensive congenital anomalies, diagnosed with FA-like disorder, homozygous for c.773G>A, p.Arg258His in RAD51C. Individual IV-2 died at 2 days old, IV-3 died at age 2 months, IV-5 (also affected) was 10 years old at time of report and did not develop cancer or hematological abnormalities. Parents confirmed heterozygous, unaffected sibling IV-1 was homozygous for WT allele. Functional: G2 arrest in fibroblasts of affected individual IV-5 was rescued by injection of WT RAD51C. Functional evidence: PMID: 36906610 Tomaszowski et al., 2023 - 'Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress' - interestingly, single gene knockouts of either Brca2 or Rad51c did not result in a Fanconi anemia phenotype in the mice. This gene is associated with AR Fanconi anemia, complementation group O, MIM:613390 and {Breast-ovarian cancer, familial, susceptibility to, 3}, MIM:613399 (OMIM accessed 9th Jan 2025). ClinGen classified the association between RAD51C and AR Fanconi anemia as Limited in 2023. |
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| Confirmed Fanconi anaemia or Bloom syndrome v1.15 | BRCA2 | Arina Puzriakova Phenotypes for gene: BRCA2 were changed from 605724 Fanconi anemia, complementation group D1; Fanconi anemia, complementation group D1, 605724 to Fanconi anemia, complementation group D1, OMIM:605724 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.20 | BRCA2 | Louise Daugherty commented on gene: BRCA2: Initial gene list (Consensus Genes for SPEC HAEM Panels 31.01.19 North West v1 FINAL.xlsx) collated by Steve Keeney Molecular Diagnostics Centre Central Manchester NHS Foundation Trust January 2019 on behalf of North West GLH for the GMS Haematology specialist test group. Gene Symbol submitted: BRCA2; Suggested initial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? No; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Phenotypes: Fanconi anemia, complementation group D1 605724; PMID(s): none submitted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.19 | BRCA2 | Steve Keeney reviewed gene: BRCA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Fanconi anemia, complementation group D1, 605724; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.18 | BRCA2 | Louise Daugherty Added phenotypes Fanconi anemia, complementation group D1, 605724 for gene: BRCA2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.16 | BRCA2 | Louise Daugherty Source North West GLH was added to BRCA2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.11 | BRCA2 | Louise Daugherty commented on gene: BRCA2: Initial gene list (Consensus Genes for Panels_Haem_SHEFFIELD-29.01.2019.xlsx) collated by Mandy Nesbitt Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Trust January 2019 on behalf of Yorkshire and North East GLH for the GMS Haematology specialist test group. Gene Symbol submitted: BRCA2; Suggested intial gene rating: Green List (high evidence); Are variants in this gene part of your current diagnostic practice? Yes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Phenotypes: 605724 Fanconi anemia, complementation group D1; PMID(s): none submitted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.10 | BRCA2 | Mandy nesbitt reviewed gene: BRCA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: 605724 Fanconi anemia, complementation group D1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.9 | BRCA2 | Louise Daugherty Added phenotypes 605724 Fanconi anemia, complementation group D1 for gene: BRCA2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.7 | BRCA2 | Louise Daugherty Source Yorkshire and North East GLH was added to BRCA2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.6 | BRCA2 | Louise Daugherty reviewed gene: BRCA2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.5 | BRCA2 | Carl Fratter reviewed gene: BRCA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.4 | BRCA2 | Louise Daugherty Source NHS GMS was added to BRCA2. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Confirmed Fanconi anaemia or Bloom syndrome v0.3 | BRCA2 |
Louise Daugherty Source Expert Review Green was added to BRCA2. Mode of inheritance for gene BRCA2 was changed from to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Fanconi anemia, complementation group D1, 605724 for gene: BRCA2 Publications for gene BRCA2 were changed from to 28185119; 14670928; 12065746; 11239453; 24395671 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| Confirmed Fanconi anaemia or Bloom syndrome v0.2 | BRCA2 |
Louise Daugherty gene: BRCA2 was added gene: BRCA2 was added to Confirmed Fanconi anaemia or Bloom syndrome. Sources: Wessex and West Midlands GLH Mode of inheritance for gene: BRCA2 was set to |
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