Insights on variant analysis in silico tools for pathogenicity prediction

Molecular biology is currently a fast-advancing science. Sequencing techniques are getting cheaper, but the interpretation of genetic variants requires expertise and computational power, therefore is still a challenge. Next-generation sequencing releases thousands of variants and to classify them, researchers propose protocols with several parameters. Here we present a review of several in silico pathogenicity prediction tools involved in the variant prioritization/classification process used by some international protocols for variant analysis and studies evaluating their efficiency

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants

PurposeThere is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará.MethodsPatients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes.ResultsA total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort.ConclusionIn this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.Fil: Vaccaro, Carlos Alberto. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López Kostner, Francisco. No especifíca;Fil: Adriana, Della Valle. Hospital Fuerzas Armadas; UruguayFil: Inez Palmero, Edenir. Hospital de cáncer de Barretos, FACISB; BrasilFil: Rossi, Benedito Mauro. Hospital Sirio Libanes; BrasilFil: Antelo, Marina. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; Argentina. Universidad Nacional de Lanús; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Carraro, Dirce Maria. No especifíca;Fil: Forones, Nora Manoukian. Universidade Federal de Sao Paulo; BrasilFil: Bohorquez, Mabel. Universidad del Tolima; ColombiaFil: Lino Silva, Leonardo S.. Instituto Nacional de Cancerologia; MéxicoFil: Buleje, Jose. Universidad de San Martín de Porres; PerúFil: Spirandelli, Florencia. No especifíca;Fil: Abe Sandes, Kiyoko. Universidade Federal da Bahia; BrasilFil: Nascimento, Ivana. No especifíca;Fil: Sullcahuaman, Yasser. Universidad Peruana de Ciencias Aplicadas; Perú. Instituto de Investigación Genomica; PerúFil: Sarroca, Carlos. Hospital Fuerzas Armadas; UruguayFil: Gonzalez, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Herrando, Alberto Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Alvarez, Karin. No especifíca;Fil: Neffa, Florencia. Hospital Fuerzas Armadas; UruguayFil: Galvão, Henrique Camposreis. Barretos Cancer Hospital; BrasilFil: Esperon, Patricia. Hospital Fuerzas Armadas; UruguayFil: Golubicki, Mariano. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Cisterna, Daniel. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: Cardoso, Florencia C.. Centro de Educación Medica E Invest.clinicas; ArgentinaFil: Tardin Torrezan, Giovana. No especifíca;Fil: Aguiar Junior, Samuel. No especifíca;Fil: Aparecida Marques Pimenta, Célia. Universidade Federal de Sao Paulo; BrasilFil: Nirvana da Cruz Formiga, María. No especifíca;Fil: Santos, Erika. Hospital Sirio Libanes; BrasilFil: Sá, Caroline U.. Hospital Sirio Libanes; BrasilFil: Oliveira, Edite P.. Hospital Sirio Libanes; BrasilFil: Fujita, Ricardo. Universidad de San Martín de Porres; PerúFil: Spirandelli, Enrique. No especifíca;Fil: Jimenez, Geiner. No especifíca;Fil: Santa Cruz Guindalini, Rodrigo. Universidade de Sao Paulo; BrasilFil: Gondim Meira Velame de Azevedo, Renata. No especifíca;Fil: Souza Mario Bueno, Larissa. Universidade Federal da Bahia; BrasilFil: dos Santos Nogueira, Sonia Tereza. No especifíca;Fil: Piñero, Tamara Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; Argentin

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazili an centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome83289298CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DO RIO GRANDE DO SUL - FAPERGSSem informaçãoSem informação2006/60402-1; 2010/51547-1; 2013/01476-9; 2014/06570-6; 2009/50575-4; 2010/51546-5; 2012/21942-116/2551-0000482-

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome

Table1_Insights on variant analysis in silico tools for pathogenicity prediction.docx

Molecular biology is currently a fast-advancing science. Sequencing techniques are getting cheaper, but the interpretation of genetic variants requires expertise and computational power, therefore is still a challenge. Next-generation sequencing releases thousands of variants and to classify them, researchers propose protocols with several parameters. Here we present a review of several in silico pathogenicity prediction tools involved in the variant prioritization/classification process used by some international protocols for variant analysis and studies evaluating their efficiency.</p

Consolidação de um Projeto Piloto de Identificação de Fatores de Risco para Câncer de Mama Hereditário de Base Populacional Vinculado ao Programa de Saúde da Família

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