Pathogenicity reclassification of two BRCA1/BRCA2 exonic duplications after identification of genomic breakpoints and tandem orientation

Pinheiro, Manuela; Peixoto, Ana; Santos, Catarina; Escudeiro, Carla; Bizarro, Susana; Pinto, Pedro; Santos, Rui; Pinto, Carla; Guerra, Joana; Silva, João; Teixeira, Manuel R.

doi:10.1016/j.cancergen.2020.09.001

Cited by 2 publications

(1 citation statement)

References 14 publications

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“…The French OncoGenetics database (FrOG_db) reports duplication of BRCA1 exons 4 to 6 in 10 patients [ 15 ] but no information on the genomic orientation of these duplications is available. However, the genomic duplication of exons 4 to 6 has been described three times in the literature: in one patient referred to a French hospital [ 16 ], in one patient from Stanford (Chinese ethnicity) [ 17 ], and in another patient studied in a Portuguese hospital [ 18 ]. The breakpoints were mapped in all three cases and matched to three distinct pairs of Alu elements, which is not surprising, since both introns 3 and 5 are long—intron 3 is the longest BRCA1 intron (9192 bp)—and contain numerous Alu repeats.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management

Ea,

Berthozat,

Dreyfus

et al. 2024

IJMS

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For patients with hereditary breast and ovarian cancer, the probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes is rare. Using targeted next-generation sequencing (NGS), we investigated a 49-year-old Caucasian woman who developed a highly aggressive breast tumor. Our analyses identified an intragenic germline heterozygous duplication in BRCA1 with an additional likely PV in the TP53 gene. The BRCA1 variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints were characterized at the nucleotide level (c.135-2578_442-1104dup). mRNA extracted from lymphocytes was amplified by RT-PCR and then Sanger sequenced, revealing a tandem duplication r.135_441dup; p.(Gln148Ilefs*20). This duplication results in the synthesis of a truncated and, most likely, nonfunctional protein. Following functional studies, the TP53 exon 5 c.472C > T; p.(Arg158Cys) missense variant was classified as likely pathogenic by the Li-Fraumeni Syndrome (LFS) working group. This type of unexpected association will be increasingly identified in the future, with the switch from targeted BRCA sequencing to hereditary breast and ovarian cancer (HBOC) panel sequencing, raising the question of how these patients should be managed. It is therefore important to record and investigate these rare double-heterozygous genotypes.

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Section: Discussionmentioning

confidence: 99%

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management

Ea,

Berthozat,

Dreyfus

et al. 2024

IJMS

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Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health

Andaluz,

Zhao,

Sinha

et al. 2024

BMC Genomics

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Background Admixture occurs between different ethnic human populations. The global colonization in recent centuries by Europeans led to the most significant admixture in human history. While admixture may enhance genetic diversity for better fitness, it may also impact on human health by transmitting genetic variants for disease susceptibility in the admixture population. The admixture by Portuguese global exploration initiated in the 15th century has reached over 20 million of Portuguese-heritage population worldwide. It provides a valuable model to study the impact of admixture on human health. BRCA1 and BRCA2 (BRCA) are two of the important tumor suppressor genes. The pathogenic variation (PV) in BRCA is well determined to cause high risk of hereditary breast and ovarian cancer. Tracing the distribution of Portuguese BRCA PV in Portuguese-heritage population will help to understand the impact of admixture on cancer susceptibility in modern humans. In this study, we analyzed the distribution of the Portuguese-originated BRCA variation in Brazilian population, which has high degree Portuguese-heritage. Methods By comprehensive data mining, standardization and annotation, we generated a Portuguese-derived BRCA variation dataset and a Brazilian-derived BRCA variation dataset. We compared the two BRCA variation datasets to identify the BRCA variants shared between the two populations. Results The Portuguese-derived BRCA variation dataset consists of 220 BRCA variants including 78 PVs from 11,482 Portuguese cancer patients, 93 (42.2%) in BRCA1 and 127 (57.7%) in BRCA2. Of the 556 Portuguese BRCA PV carriers carrying the 78 PVs, 331 (59.5%) carried the three Portuguese-BRCA founder PVs of BRCA1 c.2037delinsCC, BRCA1 c.3331_3334del and BRCA2 c.156_157insAlu. The Brazilian-derived BRCA variation dataset consists of 255 BRCA PVs from 7,711 cancer patients, 136 (53.3%) in BRCA1 and 119 (46.6%) in BRCA2. We developed an open database named dbBRCA-Portuguese (https://genemutation.fhs.um.edu.mo/dbbrca-portuguese/) and an open database named dbBRCA-Brazilian (https://genemutation.fhs.um.edu.mo/dbbrca-brazilian) to host the BRCA variation data from Portuguese and Brazilian populations. We compared the BRCA PV datasets between Portuguese and Brazilian populations, and identified 29 Portuguese-specific BRCA PVs shared between Portuguese and Brazilian populations, 14 in BRCA1 including the Portuguese founder BRCA1 c.3331_3334del and BRCA1 c.2037delinsCC, and 15 in BRCA2 including the Portuguese founder BRCA2 c.156_157insAlu. Searching the 78 Portuguese BRCA PVs in over 5,000 ancient human genomes identified evolution origin for only 8 PVs in Europeans dated between 37,470 and 3,818 years before present, confirming the Portuguese-specificity of Portuguese BRCA PVs; comparing the 78 Portuguese BRCA PVs Portuguese, 255 Brazilian BRCA PVs, and 134 African BRCA PVs showed little overlapping, ruling out the possibility that the BRCA PVs shared between Portuguese and Brazilian may also be contributed by African. Conclusion Our study provides evidence that the admixture in recent human history contributed to cancer susceptibility in modern humans.

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Pathogenicity reclassification of two BRCA1/BRCA2 exonic duplications after identification of genomic breakpoints and tandem orientation

Cited by 2 publications

References 14 publications

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management

Using Portuguese BRCA pathogenic variation as a model to study the impact of human admixture on human health

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