TY - JOUR
T1 - Double heterozygosity for TP53 and BRCA1 mutations
T2 - clinical implications in populations with founder mutations
AU - Shani, Hagit
AU - Bernstein-Molho, Rinat
AU - Laitman, Yael
AU - Netzer, Iris
AU - Friedman, Eitan
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Ashkenazi Jews
KW - BRCA1
KW - Double heterozygosity
KW - Founder mutations
KW - Pathogenic sequence variants
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=85099286469&partnerID=8YFLogxK
U2 - 10.1007/s10549-020-06084-5
DO - 10.1007/s10549-020-06084-5
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C2 - 33449224
AN - SCOPUS:85099286469
SN - 0167-6806
VL - 186
SP - 259
EP - 263
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -