Frequency of actionable Exomic secondary findings in 160 Colombian patients: Impact in the healthcare system

Rodríguez-Salgado, Liliana Elizabeth; Aldana, Claudia Tamar Silva; Medina-Méndez, Esteban; Silva, José Bareño; Arcos‐Burgos, Mauricio; Silgado-Guzmán, Daniel Felipe; Restrepo, Carlos Martín

doi:10.1016/j.gene.2022.146699

Cited by 5 publications

(2 citation statements)

References 45 publications

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“…First, the size of our project was small compared to that of other large-scale projects conducted in the western population (All of Us Research Program et al 2019;Gordon et al 2020;Van Hout et al 2020). However, our study size was comparatively large for an Asian population (Huang et al 2022;Yamaguchi-Kabata et al 2018), particularly in terms of single national population (Chan et al 2022;Jang et al 2015;Kwak et al 2017), as well as other populations (Elfatih et al 2021a;Rodríguez-Salgado et al 2022). Second, we could not determine the exact penetrance of the P/LP variants in our study population because participants who carried the P/LP variant could not be followed.…”

Section: Discussionmentioning

confidence: 94%

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study

Kim,

Cho

et al. 2023

Hum. Genet.

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Exome and genome sequencing (ES/GS) in genetic medicine and research leads to discovering genomic secondary findings (SFs) unrelated to the purpose of the primary test. There is a lack of agreement to return the SF results for individuals undergoing the test. The aim of this study is to investigate the frequency of actionable secondary findings using GS data obtained from the rare disease study and the Korean Genome and Epidemiology Study (KoGES) in the National Project of Bio Big Data pilot study. Pathogenic (P) or likely pathogenic (LP) variants of 78 SF genes recommended by the American College of Medical Genetics and Genomics (ACMG) were screened in the rare disease study and KoGES. The pathogenicity of SF gene variants was determined according to the ACMG interpretation. The overall SF rate was 3.75% for 280 individuals with 298 P/LP variants of 41 ACMG SF genes which were identified among 7472 study participants. The frequencies of genes associated with cardiovascular, cancer, and miscellaneous phenotypes were 2.17%, 1.22%, and 0.58%, respectively. The most frequent SF gene was TTN followed by BRCA2. The frequency of actionable SFs among participants with rare disease and general population participants in the Korean population presented here will assist in reporting results of medically actionable SFs in genomic medicine.

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Section: Discussionmentioning

confidence: 94%

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study

Kim,

Cho

et al. 2023

Hum. Genet.

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“…Few articles described the variant in compound heterozygosity with another PMS2 variant in patients affected with Turcot Syndrome [8] or Constitutional Mismatch Repair Deficiencies (CMMRD) [9], indicating a true occurrence of the variant in PMS2 . However, V1 has also been reported in individuals with other cancer types, including colorectal [1, 10], breast [11, 12] and prostate [13], and pseudogene interference was not ruled out in most of these studies. A recent pediatric study reported the finding of V1 in 2 patients with pilocytic astrocytoma, but after applying long-range PCR, they determined that the variant belonged to the pseudogene [14].…”

Section: Discussionmentioning

confidence: 99%

Misclassification of a frequent loss of function variant fromPMS2CLpseudogene as aPMS2variant in Brazilian patients

Campos Segura,

da Silva,

Santiago

et al. 2024

Preprint

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PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a rare LoF variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly located at PMS2 exon 13. Gene-specific PCR and transcript sequencing was performed. Among the 647 individuals, 1.8% (12) carried the investigated variants, with variant allele frequencies ranging from 15 to 34%. By visually inspecting the alignments, we confirmed that both V1 and V2 represented the same variant and through gene-specific PCR and PMS2 transcript analysis, we demonstrated that V1/V2 is actually located in the PMS2CL pseudogene. Genomic databases (ExAC and gnomAD) report an incidence of 2.5% - 5.3% of this variant in the African population. Currently, V1 is classified as ″uncertain significance″ and V2 as ″conflicting″ in ClinVar, with several laboratories classifying them as ″pathogenic″. We identified a frequent African PMS2CL LoF variant in the Brazilian population that is misclassified as a PMS2 variant. It is likely that V1/V2 have been erroneously assigned to PMS2 in several manuscripts and by clinical laboratories, underscoring a disparity-induced matter. Considering the limitations of short-read NGS differentiating between certain regions of PMS2 and PMS2CL, using complementary methodologies is imperative to provide an accurate diagnosis.

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Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals

Demir,

Saglam,

Yilmaz

et al. 2024

American J of Med Genetics Pt A

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Big data generated from exome sequencing (ES) and genome sequencing (GS) analyses can be used to detect actionable and high‐penetrance variants that are not directly associated with the primary diagnosis of patients but can guide their clinical follow‐up and treatment. Variants that are classified as pathogenic/likely pathogenic and are clinically significant but not directly associated with the primary diagnosis of patients are defined as secondary findings (SF). The aim of this study was to examine the frequency and variant spectrum of cancer‐related SF in 2020 Turkish ES data and to discuss the importance of the presence of cancer‐related SF in at‐risk family members in terms of genetic counseling and follow‐up. A total of 2020 patients from 2020 different families were evaluated by ES. SF were detected in 28 unrelated cases (1.38%), and variants in BRCA2 (11 patients) and MLH1 (4 patients) genes were observed most frequently. A total of 21 different variants were identified, with 4 of them (c.9919_9932del and c.3653del in the BRCA2 gene, c.2002A>G in the MSH2 gene, c.26_29del in the TMEM127 gene) being novel variations. In three different families, c.1189C>T (p.Gln397*) variation in BRCA2 gene was detected, suggesting that this may be a common variant in the Turkish population. This study represents the largest cohort conducted in the Turkish population, examining the frequency and variant spectrum of cancer‐related SF. With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real‐life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

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Frequency of actionable Exomic secondary findings in 160 Colombian patients: Impact in the healthcare system

Cited by 5 publications

References 45 publications

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study

Frequency of actionable secondary findings in 7472 Korean genomes derived from the National Project of Bio Big Data pilot study

Misclassification of a frequent loss of function variant fromPMS2CLpseudogene as aPMS2variant in Brazilian patients

Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals

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