A homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anemia trait

BRCA2, is a gene with a critical role in DNA repair and homologous recombination in somatic cells. Patients with biallelic alterations develop Fanconi Anemia (FA), a severe life-threatening condition  with pancytopenia and multiple malformations, while women with monoallelic alteration are at high risk to develop breast or ovarian cancer (up to 60%). Here, we surprisingly uncovered a homozygous pathogenic variant of BRCA2 in a patient with isolated primary ovarian insufficiency but without cancer or FA in all her family. We demonstrated that this alteration only mildly altered the function of the protein and that BRCA2 is expressed in the fetal ovary in meiotic germinal cells undergoing a high level of DNA breaks and consequently repair. Our work extends the phenotype of BRCA2 alteration to fully isolated POI. This has a major impact in the management and genetic counselling of patients and families. (By Prof. Micheline Misrahi, https://jmg.bmj.com/content/early/2020/06/01/jmedgenet-2019-106672 )

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