Hagit Shani1, Rinat Bernstein-Molho2,3, Yael Laitman4, Iris Netzer4, Eitan Friedman5,6,7. 1. The IVF/PGD Unit, Sheba Medical Center, Tel Hashomer, Israel. 2. Breast Cancer Unit, Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel. 3. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. 4. Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer, Israel. 5. Oncogenetics Unit, The Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer, Israel. eitan.friedman@sheba.gov.il. 6. Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. eitan.friedman@sheba.gov.il. 7. The Department of Human Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. eitan.friedman@sheba.gov.il.
Abstract
PURPOSE: The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD). METHODS: A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search. RESULTS: In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene. CONCLUSIONS: This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17.
PURPOSE: The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD). METHODS: A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search. RESULTS: In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene. CONCLUSIONS: This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17.
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