INTRODUCTION: PMS1 is part of the cluster of genes related to Mismatch repair genes (MMR) and has been used for investigation in oncogenetic panels. The MMR genes play an important role in tumor control and progression, however, the role of PMS1 in this process still poorly understood and information about its role in increasing the risk of developing a hereditary cancer predisposition syndrome (SHPC) is not completely understood.AIM: To characterize clinically and genetically cancer patients with NCCN criteria for SHPC and carriers of variants in the PMS1 gene.METHODOLOGY: A total of 368 patients suspected of having SHPC, according to the National Comprehensive Cancer Network (NCCN) criteria, were investigated using a Next-Generation Sequencing (NGS) in a panel containing 31 genes. Those that showed variation in the PMS1 gene were grouped, and the tumors were characterized in clinical and molecular aspects.RESULTS: From the 368 patients analyzed, 6.8% (25/368) patients presented Variants of Uncertain Significance (VUS) in PMS1. There was a case of Breast Cancer (BC) with a variant in PMS1, not described in ClinVar, presented in heterozygosis, probably pathogenic [Chr2:190.738,325 NM_000534: c.2578delA: p.(Arg860.Glufs*14)]. Besides, this case was associated with a family history (FH) of cancer breast cancer and melanoma. It is worth mentioning that only one patient was a man, with colorectal cancer (CRC), and his FH also was CRC in addition to stomach cancer. The only change founded was the presence of VUS NM_000534:c.1615A>G:p.(Met539Val) which was identified in 32% (8/25). This VUS was the only genetic alteration observed in 20% (5/25) patients with tumors in the breast (3), thyroid (1), CRC (1), and ovary (1). One of these patients had bilateral breast cancer and thyroid tumor. The patients had their age at diagnosis ranged from 25 to 65 years, with an average of 41 years. The carriers of variants exclusively in PMS1 [40% (10/25)] had different tumors: breast (6); CRC (3); ovary (2); lymphoma (1); thyroid (1); others 32% (n = 8/25) that presented additional VUS in different genes: [ATM (2); BARD (1); CDH1 (1); CHECK2 (1); NBN (1); APC (1); POLE (1)]. Different pathogenic variants (PV) [28% (n = 7/25)] also were identified, besides the previous PMS1 VUS described. The PV was founded in ATM (1); BRCA1 (3); NF1 (1); TP53 (1); MUTYH-heterozygosis (1), and PMS1 (1) gene. A double pathogenic variation was identified in a patient (MUTYH in heterozygosis and BRCA1). The findings in PMS1, even currently classified as VUS, should highlight observation for the clinical and familiar history. Genetic panels should be increasingly used in the investigation of SPHC.CONCLUSION: The roles of PMS1 in cancer progression need further investigations. A few numbers of reports have been identified on germline PMS1 mutations, considering defined disease phenotypes. Therefore, the performance of genetic panels, including the PMS1 gene, in SHPC further investigations will expand our knowledge and permit precise genetic counseling. Citation Format: Isabelle JoyceLima Silva-Fernandes, Clarissa Gondim Picanço-Albuquerque, Maria Claudia dos Santos Luciano, Deysi Viviana Tenazoa Wong, Maria Júlia Barbosa Bezerra, Flavio Silveira Bitencourt, Francisca Fernanda Barbosa Oliveira, Paulo Goberlanio de Barros Silva, Rosane Oliveira Sant´anna, Marcos Venicio Alves Lima. Pms1 gene: A new risk-mutation description? [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-30.
e22528 Background: The familiar history is indispensable to clinical investigation during genetic counseling and the new molecular techniques allowed the identification of hereditary cancer predisposition syndromes (CPS). However, the classification systems of these syndromes are difficulty and very complex. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases to reduce the subjectivity bias of mutation variants classified as risk. Methods: To show the difficulty of classification of these variants we describe a case report of a family from countryside of Brazil in which there is a high rate of inbreeding. This family has three brothers with polyposis and colorectal cancer between 51 and 60 years-old. Results: The index-case had multiple polyps, developed colorectal cancer at 51 years-old and had a familiar history of two brother dead by colorectal cancer after polyposis and nine brother without familiar history of cancer, a father dead at 38 years-old by non-specific lung-disease and a mother alive at 83 years-old. There was no description of other cases of cancer among uncles and grandparents. The index-case performe a NSG genetic painel to CPS and showed a homozygosis variant in MUTYH gene: NM_001048174.1: c.253T > C:p.(Trp85Arg), that was classified as variant of uncertain significance (VUS). MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors and may be considered a cell protective factor and is associated with MUTYH-related polyposis (MAP). MAP is an autosomal recessive CPS and presents a phenotype that overlaps attenuated polyposis and familial adenomatous polyposis, increasing the risk of colorectal cancer in 43-63% up to 60 years or 80% if there is no surveillance/tracking. In view of the family history that suggests autosomal recessive inheritance, with a homozygous variant absent in the database of population controls (gnomAD) and in which in silico predictors indicate the effect of this variant as deleterious, the management of this family must be carried out considering it as a potential high-risk pathogenic variant. Conclusions: While the classification criteria for the variants are being refined, we reinforce the importance of a careful family history in the approach to CPS in order to offer an appropriate clinal conduct in the prevention of hereditary cancer.
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