Segregation analysis of the BRCA2 c.9227G>T variant in multiple families suggests a pathogenic role in breast and ovarian cancer predisposition

Simona Agata, Silvia Tognazzo, Elisa Alducci, Laura Matricardi, Lidia Moserle, Daniela Barana, Marco Montagna

Research output: Contribution to journalArticlepeer-review

Abstract

Classification of variants in the BRCA1 and BRCA2 genes has a major impact on the clinical management of subjects at high risk for breast and ovarian cancer. The identification of a pathogenic variant allows for early detection/prevention strategies in healthy carriers as well as targeted treatments in patients affected by BRCA-associated tumors. The BRCA2 c.9227G>T p.(Gly3076Val) variant recurs in families from Northeast Italy and is rarely reported in international databases. This variant substitutes the evolutionary invariant glycine 3076 with a valine in the DNA binding domain of the BRCA2 protein, thus suggesting a high probability of pathogenicity. We analysed clinical and genealogic data of carriers from 15 breast/ovarian cancer families in whom no other pathogenic variants were detected. The variant was shown to co-segregate with breast and ovarian cancer in the most informative families. Combined segregation data led to a likelihood ratio of 81,527:1 of pathogenicity vs. neutrality. We conclude that c.9227G>T is a BRCA2 pathogenic variant that recurs in Northeast Italy. It can now be safely used for the predictive testing of healthy family members to guide preventive surgery and/or early tumor detection strategies, as well as for PARP inhibitors treatments in patients with BRCA2-associated tumors.

Original languageEnglish
Pages (from-to)13987
Number of pages6
JournalSci. Rep.
Volume10
Issue number1
DOIs
Publication statusPublished - Aug 19 2020

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • BRCA1 Protein/genetics
  • BRCA2 Protein/genetics
  • Breast Neoplasms/diagnosis
  • Family Health
  • Female
  • Genetic Predisposition to Disease/genetics
  • Genetic Testing
  • Humans
  • Male
  • Middle Aged
  • Ovarian Neoplasms/diagnosis
  • Pedigree
  • Polymorphism, Single Nucleotide

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