Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients

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Grasel, Rebeca Silveira ; Felicio, Paula Silva ; de Paula, Andre Escremim ; Campacci, Natalia ; de Oliveira Garcia, Felipe Antonio ; de Andrade, Edilene Santos ; Evangelista, Adriane Feijo ; Fernandes, Gabriela Carvalho ; Sabato, Cristina da Silva ; De Marchi, Pedro ; Souza, Cristiano de Padua ; Andrade de Paula, Claudia Alessandra ; Torrezan, Giovana Tardin ; Reis Galvao, Henrique de Campos ; Carraro, Dirce Maria ; Palmero, Edenir Inez

• Document type: Journal article
• Source: FRONTIERS IN ONCOLOGY; v. 10, p. 10-pg., 2020-10-02.

Abstract

The use of gene panels introduces a new dilemma in the genetics field due to the high frequency of variants of uncertain significance (VUS). The objective of this study was to provide evidence that may help in the classification of these germline variants in terms of their clinical impact and association with the disease in question. A total of 52 unrelated women at-risk for HBOC and negative forBRCA1/BRCA2pathogenic variants were evaluated through a gene panel comprising 14 breast and/or ovarian cancer susceptibility genes. Of the 453 germline variants identified, 15 variants (classes 3, 4, and 5) in theATM, BRIP1, CHEK2, MRE11A, MUTHY, PALB2, RAD50, andRAD51Cgenes were evaluated via databases, co-segregation studies and loss of heterozygosity in the tumor. The co-segregation analysis allowed the establishment of an association with the presence of variants and the risk of cancer for variant c.316C>T in theBRIP1gene. Four variants of uncertain significance showed loss of heterozygosity in the tumor (ATMc.4709T>C;CHEK2c.1036C>T;PALB2c.1001A>G, andRAD50c.281T>C), which is an indication of pathogenicity. Thus, the present study provides novel evidence that favors the association of variants in moderate-risk genes with the development of hereditary breast cancer. (AU)

• FAPESP's process: 13/24633-2 - Molecular characterization of at high risk families for hereditary breast cancer, negatives for BRCA1/BRCA2: looking for the BRCAx
• Grantee: Edenir Inêz Palmero
• Support Opportunities: Regular Research Grants