Reclassification of clinical exome data leads to significant clinical assessment changes in almost half of the patients

Year 2023, Volume: 48 Issue: 3, 1072 - 1080, 30.09.2023

Umut Arda Bayraktar , Feride İffet Şahin , Mert Polat , Yunus Kasım Terzi

https://doi.org/10.17826/cumj.1316760

Abstract

Purpose: With the global accumulation of genetic/clinical data, we are understanding the clinical significance of the reclassification of pathogenicity for gene variants. We hypothesized that this evolution in classification(s) may cause clinically-relevant discrepancies in the genetic risk assessment of subjects. In this study, we sought to reclassify the clinical exome sequence (CES) data of our patients to assess whether these changes would have clinical significance.
Materials and Methods: The study included CES data of 23 cases diagnosed with cancer or familial cancer predisposition. The variants were first classified in 2020 and then reclassified a year after based on the ACMG database. Chart reviews were performed to record clinical history and interventions.
Results: In the first classification of CES data, a total of 80 variants were identified as being not benign (26 likely pathogenic/pathogenic and 54 variants of undetermined significance (VUS)). The clinical significance of fifteen variants (19%) changed after reclassification in 10 patients (43%). The only upgraded variant was the c.9097 dup in exon 23 of BRCA2 gene (likely pathogenic to pathogenic). Fourteen variants were downgraded at reanalysis in 9 patients: from pathogenic to likely pathogenic (2 variants), pathogenic to VUS (2), likely pathogenic to VUS (4), and VUS to benign (6).
Conclusion: Considering that the clinical significance of CES data changed due to reclassification in almost half of the studied patients, we believe genetic variant-related data should be assessed at regular intervals, regardless of follow-up status in the clinic.

Keywords

cancer, clinical exome sequencing, likely pathogenic/pathogenic variants

Project Number

KA21/303

Thanks

All authors contributed to the study’s conception and design. The first draft of the manuscript was written by Umut Arda Bayraktar, Feride Iffet Sahin, Yunus Kazım Terzi and all authors commented on previous versions of the manuscript. All authors read and approve the final manuscript.

Klinik ekzom verilerinin yeniden sınıflandırılması hastaların yaklaşık olarak yarısında klinik değerlendirmede anlamlı değişmelere neden olmaktadır

Abstract

Amaç: Gen varyantlarının patojenitelerindeki değişmelerin (yeniden sınıflandırma) klinik önemleri genetik/klinik veriler arttıkça giderek daha çok anlaşılmaktadır. Bize göre bu durum hastaların varyantları yeniden sınıflandırıldığında genetik risk değerlendirmesinde kliniksel açıdan önemli tutarsızlıklara yol açabilmektedir. Bu çalışmada, hastalarımızın klinik ekzom sekanslama (CES) verilerini yeniden sınıflandırarak bu verilerin klinik açıdan anlamlılığını değerlendirdik.
Gereç ve Yöntem: Kendisinde kanser teşhis edilmiş veya ailesel kanser yatkınlığı olan 23 hastanın CES verileri incelendi. İncelenen varyantlar ACMG veri tabanı kullanılarak 2020 yılında sınıflandırıldıktan sonra ertesi yıl tekrardan sınıflandırıldı. Hastaların klinik hikayelerini ve yapılan müdahaleleri kaydedebilmek için hasta dosyaları incelendi.
Bulgular: CES verilerinin ilk incelenmesinde, benign olmayan 80 varyant tespit edilmiştir (26 olası patojenik/patojenik ve 54 önemi bilinmeyen varyant (VUS)). Yeniden sınıflandırma sonrası 10 hastada (%43) 15 varyantın (%19) klinik önemi değişmiştir. Klinik önemi artan tek varyant BRCA2 geninin ekzon 23’ündeki c.9097 dup varyantı olmuştur (olası patojenikten patojeniğe). Yeniden analiz sonrası dokuz hastada 14 varyantın klinik önemi azalmıştır: patojenikten olası patojeniğe (2 varyant), patojenikten VUS’a (2 varyant), olası patojenikten VUS’a (4 varyant) ve VUS’dan benigne (6 varyant).
Sonuç: Çalışılan hastaların yaklaşık yarısında CES verilerinin klinik öneminin yeniden analizler sonrası değiştiği düşünüldüğünde, genetik varyantlar ile ilişkili verilerin klinikteki takip durumlarından bağımsız olarak düzenli aralıklarla değerlendirilmesi gerektiğine inanmaktayız.

Keywords

Kanser, klinik ekzom sekanslama, olası patojenik/patojenik varyantlar

Project Number

KA21/303

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