Opportunistic genetic screening increases the diagnostic yield and is medically valuable for care of patients and their relatives with hereditary cancer

Sep 28, 2026

Background Multigene panel testing by next-generation sequencing enables detection of germline pathogenic or likely pathogenic variants beyond genes tied to a specific cancer phenotype. Opportunistic genetic screening in patients suspected of hereditary cancer can reveal incidental findings. Methods Multigene panel testing followed Catalan Health Service criteria; variant classification used ACMG-AMP and UK Cancer Variant Interpretation Group guidance. Results Incidental findings occurred in 10 of 817 patients, mainly actionable genes, including diverse variant types. Conclusions Opportunistic screening increased diagnostic yield and supports early diagnosis and prevention.

LanguageEnglish

CategoryHealthcare

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Background

Methods

Results

Conclusions

Introduction

Hereditary cancer genetics and sequencing approaches

Multigene panel testing and yield limitations

Cancer genetics Original research Opportunistic genetic screening increases the diagnostic yield and is medically valuable for care of patients and their relatives with hereditary cancer Sara Fernández-Castillejo , 1 Bàrbara Roig, 1 Mireia Melé, 1 Sara Serrano, 1 Mònica Salvat, 1 Montserrat Querol, 1 Joan Brunet ,2,3 Marta Pineda ,2 Adela Cisneros,4 David Parada,5 Joan Badia, 1 Joan Borràs, 1 Marta Rodríguez-Balada , 1 Josep Gumà 1 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx](http://dx). [doi.org/10.1136/jmg-2023-](doi.org/10.1136/jmg-2023-)[ ](doi.org/10.1136/jmg-2023-)[109389](109389)) . For numbered affiliations see end of article. Correspondence to Dr Marta Rodríguez-Balada, IISPV, Reus, 43204, Spain; marta. rodriguez@salutsantjoan. cat SF-C and BR contributed equally. Received 10 May 2023 Accepted 23 July 2023 Published Online First 17 August 2023 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. To cite: Fernández-Castillejo S, Roig B, Melé M, et al. J Med Genet 2024;61:69–77 . ABSTRACT Background Multigene panel testing by nextgeneration sequencing (MGP-NGS) enables the detection of germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes beyond those associated with a certain cancer phenotype. Opportunistic genetic screening based on MGP-NGS in patients with suspicion of hereditary cancer reveals these incidental findings (IFs) . Methods MGP-NGS was performed in patients who fulfilled the clinical criteria to undergo genetic testing according to the Catalan Health Service guidelines. Variants were classified following the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and the Cancer Variant Interpretation Group UK guidelines. Results IFs were identified in 10 (1 . 22%) of the 817 patients who underwent MGP-NGS. The mean age at cancer diagnosis was 49 .4±9 . 5 years. Three IFs (30 .0%) were detected in PMS2, two (20 .0%) in ATM and TP53 and one (10 .0%) in MSH6, NTHL1 and VHL. Seven (70 .0%) IFs were single-nucleotide substitutions, two (20 .0%) were deletions and one (10 .0%) was a duplication. Three (30 .0) IFs were located in intronic regions, three (30.3%) were nonsense, two (20.0%) were frameshift and two (20 .0%) were missense variations. Six (60 .0%) IFs were classified as PVs and four (40 .0%) as LPVs. Conclusions Opportunistic genetic screening increased the diagnostic yield by 1. 22% in our cohort. Most of the identified IFs were present in clinically actionable genes (n=7; 70.0%), providing these families with an opportunity to join cancer early detection programmes, as well as secondary cancer prevention. IFs might facilitate the diagnosis of asymptomatic individuals and the early management of cancer once it develops. INTRODUCTION The development of next-generation sequencing (NGS) marks a turning point in the genetic diagnosis field. Compared with the gold standard technique for mutation analysis in cancer diagnosis, the Sanger sequencing method, NGS can sequence a large number of DNA regions while being timeeffective and cost-effective at the same time. NGS | WHAT IS ALREADY KNOWN ON THIS TOPIC | | --- | | ⇒ Hereditary cancer syndromes are caused by inherited alterations in >200 cancer-related genes, most of which are involved in cell cycle control and DNA repair; however, in only 5%–10% of cases with a hereditary cancer suspicion, the disease-causing alteration is identified.
⇒ Opportunistic genetic screening through multigene panel testing by next-generation sequencing (MGP-NGS) can unveil unexpected pathogenic or likely pathogenic variants (PVs/ LPVs) initially inconsistent with the personal and familial cancer history of the patient.
WHAT THIS STUDY ADDS | | ⇒ Our results confirm that MGP-NGS performed on patients with persona

FAQs

What is opportunistic genetic screening in hereditary cancer evaluation?

It uses multigene panel testing by next-generation sequencing in patients meeting clinical testing criteria to uncover incidental pathogenic or likely pathogenic variants beyond the cancer phenotype-linked genes.

How often did incidental findings occur in this cohort?

Incidental findings were identified in 10 of 817 patients undergoing multigene panel testing, corresponding to an overall yield of 1.22%.

Why are the identified incidental findings clinically important?

Most were in clinically actionable genes, enabling potential benefits for patients and relatives through early detection programs and secondary cancer prevention, and supporting early management when cancer develops.

Sep 28, 2026

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