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Article ; Online: SpliceAI-10k calculator for the prediction of pseudoexonization, intron retention, and exon deletion.

Canson, Daffodil M / Davidson, Aimee L / de la Hoya, Miguel / Parsons, Michael T / Glubb, Dylan M / Kondrashova, Olga / Spurdle, Amanda B

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 4

Abstract: Summary: SpliceAI is a widely used splicing prediction tool and its most common application relies on the maximum delta score to assign variant impact on splicing. We developed the SpliceAI-10k calculator (SAI-10k-calc) to extend use of this tool to ... ...

Abstract	Summary: SpliceAI is a widely used splicing prediction tool and its most common application relies on the maximum delta score to assign variant impact on splicing. We developed the SpliceAI-10k calculator (SAI-10k-calc) to extend use of this tool to predict: the splicing aberration type including pseudoexonization, intron retention, partial exon deletion, and (multi)exon skipping using a 10 kb analysis window; the size of inserted or deleted sequence; the effect on reading frame; and the altered amino acid sequence. SAI-10k-calc has 95% sensitivity and 96% specificity for predicting variants that impact splicing, computed from a control dataset of 1212 single-nucleotide variants (SNVs) with curated splicing assay results. Notably, it has high performance (≥84% accuracy) for predicting pseudoexon and partial intron retention. The automated amino acid sequence prediction allows for efficient identification of variants that are expected to result in mRNA nonsense-mediated decay or translation of truncated proteins. Availability and implementation: SAI-10k-calc is implemented in R (https://github.com/adavi4/SAI-10k-calc) and also available as a Microsoft Excel spreadsheet. Users can adjust the default thresholds to suit their target performance values.
MeSH term(s)	Introns ; Exons ; RNA Splicing ; RNA, Messenger/metabolism ; Amino Acid Sequence
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2023-04-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad179
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Article ; Online: Comprehensive splicing analysis of the alternatively spliced CHEK2 exons 8 and 10 reveals three enhancer/silencer-rich regions and 38 spliceogenic variants.

Sanoguera-Miralles, Lara / Llinares-Burguet, Inés / Bueno-Martínez, Elena / Ramadane-Morchadi, Lobna / Stuani, Cristiana / Valenzuela-Palomo, Alberto / García-Álvarez, Alicia / Pérez-Segura, Pedro / Buratti, Emanuele / de la Hoya, Miguel / Velasco-Sampedro, Eladio A

The Journal of pathology

2024 Volume 262, Issue 4, Page(s) 395–409

Abstract: Splicing is controlled by a large set of regulatory elements (SREs) including splicing enhancers and silencers, which are involved in exon recognition. Variants at these motifs may dysregulate splicing and trigger loss-of-function transcripts associated ... ...

Abstract	Splicing is controlled by a large set of regulatory elements (SREs) including splicing enhancers and silencers, which are involved in exon recognition. Variants at these motifs may dysregulate splicing and trigger loss-of-function transcripts associated with disease. Our goal here was to study the alternatively spliced exons 8 and 10 of the breast cancer susceptibility gene CHEK2. For this purpose, we used a previously published minigene with exons 6-10 that produced the expected minigene full-length transcript and replicated the naturally occurring events of exon 8 [Δ(E8)] and exon 10 [Δ(E10)] skipping. We then introduced 12 internal microdeletions of exons 8 and 10 by mutagenesis in order to map SRE-rich intervals by splicing assays in MCF-7 cells. We identified three minimal (10-, 11-, 15-nt) regions essential for exon recognition: c.863_877del [ex8, Δ(E8): 75%] and c.1073_1083del and c.1083_1092del [ex10, Δ(E10): 97% and 62%, respectively]. Then 87 variants found within these intervals were introduced into the wild-type minigene and tested functionally. Thirty-eight of them (44%) impaired splicing, four of which (c.883G>A, c.883G>T, c.884A>T, and c.1080G>T) induced negligible amounts (<5%) of the minigene full-length transcript. Another six variants (c.886G>A, c.886G>T, c.1075G>A, c.1075G>T, c.1076A>T, and c.1078G>T) showed significantly strong impacts (20-50% of the minigene full-length transcript). Thirty-three of the 38 spliceogenic variants were annotated as missense, three as nonsense, and two as synonymous, underlying the fact that any exonic change is capable of disrupting splicing. Moreover, c.883G>A, c.883G>T, and c.884A>T were classified as pathogenic/likely pathogenic variants according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based criteria. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
MeSH term(s)	Humans ; RNA Splicing/genetics ; Exons/genetics ; United Kingdom ; Alternative Splicing ; Checkpoint Kinase 2/genetics
Chemical Substances	CHEK2 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 2 (EC 2.7.1.11)
Language	English
Publishing date	2024-02-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6243
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Article ; Online: Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in BRCA2

Hidalgo Mayoral, Irene / Almeida Santiago, Ainhoa / Sánchez-Zapardiel, Jose Manuel / Hidalgo Calero, Beatriz / de la Hoya, Miguel / Gómez-Sanz, Alicia / de Miguel Reyes, Montserrat / Robles, Luis

Genes (Basel). 2023 Feb. 15, v. 14, no. 2

2023

Abstract: Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC ... ...

Abstract	Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).
Keywords	algorithms ; breasts ; etiology ; gene frequency ; genes ; heterozygosity ; ovarian neoplasms ; prioritization ; progeny ; risk ; tumor suppressor proteins
Language	English
Dates of publication	2023-0215
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14020502
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Unexpected Findings in Hereditary Breast and Ovarian Cancer Syndrome: Low-Level Constitutional Mosaicism in

Hidalgo Mayoral, Irene / Almeida Santiago, Ainhoa / Sánchez-Zapardiel, Jose Manuel / Hidalgo Calero, Beatriz / de la Hoya, Miguel / Gómez-Sanz, Alicia / de Miguel Reyes, Montserrat / Robles, Luis

Genes

2023 Volume 14, Issue 2

Abstract	Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the
MeSH term(s)	Humans ; Female ; Hereditary Breast and Ovarian Cancer Syndrome/genetics ; Genes, BRCA2 ; Mosaicism ; Mutation ; Ovarian Neoplasms/genetics ; BRCA2 Protein/genetics
Chemical Substances	BRCA2 protein, human ; BRCA2 Protein
Language	English
Publishing date	2023-02-15
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes14020502
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Article: APPLICATION OF THE ACMG/AMP FRAMEWORK TO CAPTURE EVIDENCE RELEVANT TO PREDICTED AND OBSERVED IMPACT ON SPLICING: RECOMMENDATIONS FROM THE CLINGEN SVI SPLICING SUBGROUP.

Walker, Logan C / de la Hoya, Miguel / Wiggins, George A R / Lindy, Amanda / Vincent, Lisa M / Parsons, Michael T / Canson, Daffodil M / Bis-Brewer, Dana / Cass, Ashley / Tchourbanov, Alexander / Zimmermann, Heather / Byrne, Alicia B / Pesaran, Tina / Karam, Rachid / Harrison, Steven / Spurdle, Amanda B

medRxiv : the preprint server for health sciences

2023

Abstract: The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1 (null variant in a gene ... ...

Abstract	The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1 (null variant in a gene where loss-of-function is the mechanism of disease), PS3 (functional assays show damaging effect on splicing), PP3 (computational evidence supports a splicing effect), BS3 (functional assays show no damaging effect on splicing), BP4 (computational evidence suggests no splicing impact), and BP7 (silent change with no predicted impact on splicing). However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation (SVI) Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. Our study utilised empirically derived splicing evidence to: 1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, 2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and 3) exemplify methodology to calibrate bioinformatic splice prediction tools. We propose repurposing of the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely BP7 may be used to capture RNA results demonstrating no impact on splicing for both intronic and synonymous variants, and for missense variants if protein functional impact has been excluded. Furthermore, we propose that the PS3 and BS3 codes are applied only for well-established assays that measure functional impact that is not directly captured by RNA splicing assays. We recommend the application of PS1 based on similarity of predicted RNA splicing effects for a variant under assessment in comparison to a known Pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA assay evidence described aim to help standardise variant pathogenicity classification processes and result in greater consistency when interpreting splicing-based evidence.
Language	English
Publishing date	2023-02-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.24.23286431
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Article ; Online: Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants.

Sanoguera-Miralles, Lara / Valenzuela-Palomo, Alberto / Bueno-Martínez, Elena / Esteban-Sánchez, Ada / Lorca, Víctor / Llinares-Burguet, Inés / García-Álvarez, Alicia / Pérez-Segura, Pedro / Infante, Mar / Easton, Douglas F / Devilee, Peter / Vreeswijk, Maaike P G / de la Hoya, Miguel / Velasco-Sampedro, Eladio A

Clinical chemistry

2023 Volume 70, Issue 1, Page(s) 319–338

Abstract: Background: Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes.: Methods!# ...

Abstract	Background: Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes. Methods: A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells. Results: Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5'UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition. Conclusions: Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.
MeSH term(s)	Humans ; Female ; Alternative Splicing ; RNA Splicing ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Exons ; Introns ; RNA Splice Sites/genetics ; Checkpoint Kinase 2/genetics
Chemical Substances	RNA Splice Sites ; CHEK2 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 2 (EC 2.7.1.11)
Language	English
Publishing date	2023-09-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80102-1
ISSN	1530-8561 ; 0009-9147
ISSN (online)	1530-8561
ISSN	0009-9147
DOI	10.1093/clinchem/hvad125
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Article: Splicing Analysis of 16

Valenzuela-Palomo, Alberto / Sanoguera-Miralles, Lara / Bueno-Martínez, Elena / Esteban-Sánchez, Ada / Llinares-Burguet, Inés / García-Álvarez, Alicia / Pérez-Segura, Pedro / Gómez-Barrero, Susana / de la Hoya, Miguel / Velasco-Sampedro, Eladio A

Cancers

2022 Volume 14, Issue 18

Abstract: PALB2 loss-of-function variants are associated with significant increased risk of breast cancer as well as other types of tumors. Likewise, splicing disruptions are a common mechanism of disease susceptibility. Indeed, we previously showed, by minigene ... ...

Abstract	PALB2 loss-of-function variants are associated with significant increased risk of breast cancer as well as other types of tumors. Likewise, splicing disruptions are a common mechanism of disease susceptibility. Indeed, we previously showed, by minigene assays, that 35 out of 42 PALB2 variants impaired splicing. Taking advantage of one of these constructs (mgPALB2_ex1-3), we proceeded to analyze other variants at exons 1 to 3 reported at the ClinVar database. Thirty-one variants were bioinformatically analyzed with MaxEntScan and SpliceAI. Then, 16 variants were selected for subsequent RNA assays. We identified a total of 12 spliceogenic variants, 11 of which did not produce any trace of the expected minigene full-length transcript. Interestingly, variant c.49-1G > A mimicked previous outcomes in patient RNA (transcript ∆(E2p6)), supporting the reproducibility of the minigene approach. A total of eight variant-induced transcripts were characterized, three of which (∆(E1q17), ∆(E3p11), and ∆(E3)) were predicted to introduce a premature termination codon and to undergo nonsense-mediated decay, and five (▼(E1q9), ∆(E2p6), ∆(E2), ▼(E3q48)-a, and ▼(E3q48)-b) maintained the reading frame. According to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, which integrates mgPALB2 data, six PALB2 variants were classified as pathogenic/likely pathogenic, five as VUS, and five as likely benign. Furthermore, five ±1,2 variants were catalogued as VUS because they produced significant proportions of in-frame transcripts of unknown impact on protein function.
Language	English
Publishing date	2022-09-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14184541
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Article: Minigene Splicing Assays Identify 20 Spliceogenic Variants of the Breast/Ovarian Cancer Susceptibility Gene

Sanoguera-Miralles, Lara / Bueno-Martínez, Elena / Valenzuela-Palomo, Alberto / Esteban-Sánchez, Ada / Llinares-Burguet, Inés / Pérez-Segura, Pedro / García-Álvarez, Alicia / de la Hoya, Miguel / Velasco-Sampedro, Eladio A

Cancers

2022 Volume 14, Issue 12

Abstract: RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 ( ... ...

Abstract	RAD51C loss-of-function variants are associated with an increased risk of breast and ovarian cancers. Likewise, splicing disruptions are a frequent mechanism of gene inactivation. Taking advantage of a previous splicing-reporter minigene with exons 2-8 (mgR51C_ex2-8), we proceeded to check its impact on the splicing of candidate ClinVar variants. A total of 141 RAD51C variants at the intron/exon boundaries were analyzed with MaxEntScan. Twenty variants were selected and genetically engineered into the wild-type minigene. All the variants disrupted splicing, and 18 induced major splicing anomalies without any trace or minimal amounts (<2.4%) of the minigene full-length (FL) transcript. Twenty-seven transcripts (including the wild-type and r.904A FL transcripts) were identified by fluorescent fragment electrophoresis; of these, 14 were predicted to truncate the RAD51C protein, 3 kept the reading frame, and 8 minor isoforms (1.1−4.7% of the overall expression) could not be characterized. Finally, we performed a tentative interpretation of the variants according to an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme, classifying 16 variants as likely pathogenic. Minigene assays have been proven as valuable tools for the initial characterization of potential spliceogenic variants. Hence, minigene mgR51C_ex2-8 provided useful splicing data for 40 RAD51C variants.
Language	English
Publishing date	2022-06-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14122960
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Article: Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants.

bioRxiv : the preprint server for biology

2023

Abstract: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. ... ...

Abstract	Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all Summary: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to several types of cancer. However, variants of uncertain significance (VUS) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.14.571597
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Article ; Online: A New Set of in Silico Tools to Support the Interpretation of ATM Missense Variants Using Graphical Analysis.

Porras, Luz-Marina / Padilla, Natàlia / Moles-Fernández, Alejandro / Feliubadaló, Lidia / Santamariña-Pena, Marta / Sánchez, Alysson T / López-Novo, Anael / Blanco, Ana / de la Hoya, Miguel / Molina, Ignacio J / Osorio, Ana / Pineda, Marta / Rueda, Daniel / Ruiz-Ponte, Clara / Vega, Ana / Lázaro, Conxi / Díez, Orland / Gutiérrez-Enríquez, Sara / de la Cruz, Xavier

The Journal of molecular diagnostics : JMD

2023 Volume 26, Issue 1, Page(s) 17–28

Abstract: Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To ... ...

Abstract	Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of prediction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information.
MeSH term(s)	Humans ; Female ; Reproducibility of Results ; Mutation, Missense/genetics ; Genomics ; Breast Neoplasms/genetics ; Ataxia Telangiectasia Mutated Proteins/genetics
Chemical Substances	ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2023-10-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2023.09.009
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