Impact of High-to-Moderate Penetrance Genes on Genetic Testing: Looking over Breast Cancer

Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2, many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel...

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Published in:Genes 2023-07, Vol.14 (8), p.1530
Main Authors: Turchiano, Antonella, Piglionica, Marilidia, Martino, Stefania, Bagnulo, Rosanna, Garganese, Antonella, De Luisi, Annunziata, Chirulli, Stefania, Iacoviello, Matteo, Stasi, Michele, Tabaku, Ornella, Meneleo, Eleonora, Capurso, Martina, Crocetta, Silvia, Lattarulo, Simone, Krylovska, Yevheniia, Lastella, Patrizia, Forleo, Cinzia, Stella, Alessandro, Bukvic, Nenad, Simone, Cristiano, Resta, Nicoletta
Format: Article
Language:English
Subjects:
Alternative splicing
BRCA1 protein
BRCA2 protein
Breast cancer
Cancer
Clear cell-type renal cell carcinoma
Disease susceptibility
Family medical history
Genes
Genetic aspects
Genetic screening
Genetic testing
Genomes
Mammography
Melanoma
Mutation
Patients
Software
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Summary:Breast cancer (BC) is the most common cancer and the leading cause of cancer death in women worldwide. Since the discovery of the highly penetrant susceptibility genes BRCA1 and BRCA2, many other predisposition genes that confer a moderate risk of BC have been identified. Advances in multigene panel testing have allowed the simultaneous sequencing of BRCA1/2 with these genes in a cost-effective way. Germline DNA from 521 cases with BC fulfilling diagnostic criteria for hereditary BC were screened with multigene NGS testing. Pathogenic (PVs) and likely pathogenic (LPVs) variants in moderate penetrance genes were identified in 15 out of 521 patients (2.9%), including 2 missense, 7 non-sense, 1 indel, and 3 splice variants, as well as two different exon deletions, as follows: ATM (n = 4), CHEK2 (n = 5), PALB2 (n = 2), RAD51C (n = 1), and RAD51D (n = 3). Moreover, the segregation analysis of PVs and LPVs into first-degree relatives allowed the detection of CHEK2 variant carriers diagnosed with in situ melanoma and clear cell renal cell carcinoma (ccRCC), respectively. Extended testing beyond BRCA1/2 identified PVs and LPVs in a further 2.9% of BC patients. In conclusion, panel testing yields more accurate genetic information for appropriate counselling, risk management, and preventive options than assessing BRCA1/2 alone.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes14081530