Prevalence of pathogenic variants in non-BRCA genes and their impact on clinical practice in Argentina.
Authors: Martin Claudia Alejandra , Miretti Virginia , Maldonado Emilia , Canonero Ivana , Pabletich Florencia , Ceschin Danilo , Andreoli Veronica 
Published: June 2023

e22534

Background: The use of NGS has made it easier and more cost-effective to analyze genes associated with hereditary cancer predisposition syndromes. Germline alterations in breast cancer (BC) have an estimated prevalence of 10.7% of Pathogenic Variant or Likely Pathogenic (P/LP), with up to 8.0% in BRCA1/2 and 2.7% in CHEK2, ATM and PALB2 genes; they increase the risk of cancer 2 to 5 times. To date, two studies of P/LP in genes non-BRCA1/2 have been conducted in Argentina with frequencies of 4.5 and 4.7% in patients with personal and/or family history of BC. Methods: We report the frequency of P/LP in non-BRCA1/2 genes in patients with hereditary cancer criteria referred to the Oncogenetics Program at Hospital Privado Universitario de Córdoba between 01/2016 and 12/2022. A retrospective analysis was conducted on patients with BC, ovarian cancer (OC), pancreatic cancer (PaC), or prostate cancer (PC) who had clinical criteria for hereditary cancer. NGS and/or Sanger methods were used to sequence the samples, and the frequency of P/LP, novel P, and their association with other variants were collected and associated with the clinical features of the index case. Results: Of 283 cases studied, 85 (30.0%) were P/LP, with 53 (18.7%) detected in BRCA1/2 and 32 (11.3%) in other genes. Among the 32 mutations found in non-BRCA1/2 genes, the frequency of P/LP was 4.59% for PALB2 and 2.47% for CHEK2, 1.06% for TP53, 0.7% for MUTHY and 0.35% each for ATM, BRIP1, FANCC, MLH1, MSH2, FANCM and PTEN. The cases studied correspond to BC (75%), PaC (9.3%) and asymptomatic patients (15.7%), two of which belonged to families with an identified mutation in PALB2, other two in CHEK2, and one with no available index case with a mutation in ATM. The age at diagnosis in the cases with personal history was 44.5 years (20-66) with a very early age in the cases with TP53 mutations and two cases with PALB2 variants. Of the total mutations in non-BRCA1/2 genes, two were found to be associated with other pathogenic mutations and 12 were associated with VUS. Within our study, four remarkable findings were identified in PALB2 gene: 1) five unrelated families share the pathogenic c.1653T > A; 2) two unrelated families share the pathogenic c.1959T > A; 3) the novel c.2872_2875del LP variant was detected and 4) the frequency of the variant c.1653T > A suggests the possibility of a founder effect. Our study shows a higher frequency of P/LP in non-BRCA genes than those reported in Argentina and Latin America, which may be due to the selection of a population with family and/or personal history of cancer. Conclusions: It is important to perform multi-gene testing including moderate-penetrance genes to determine the hereditary susceptibility to cancer in our population and to identify vulnerable groups that require more specialized surveillance than the general population. This will help individuals with a higher risk of developing cancer to take effective preventive actions.