Novel truncating germline variant reinforces as a susceptibility gene for familial non-medullary thyroid cancer.

Background: It has long been observed that there are families in which non-medullary thyroid cancer (NMTC) occurs, but few syndromes and genes have been described to date. Proteins in the shelterin complex have been implied in cancer. Here, we have studied shelterin genes in families affected by NMTC (FNMTC).

A Novel Intragenic Duplication in the Gene Underlying a Case of Cornelia de Lange Syndrome.

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome.

Role of Splicing Regulatory Elements and In Silico Tools Usage in the Identification of Deep Intronic Splicing Variants in Hereditary Breast/Ovarian Cancer Genes.

The contribution of deep intronic splice-altering variants to hereditary breast and ovarian cancer (HBOC) is unknown. Current computational in silico tools to predict spliceogenic variants leading to pseudoexons have limited efficiency. We assessed the performance of the SpliceAI tool combined with ESRseq scores to identify spliceogenic deep intronic variants by affecting cryptic sites or splicing regulatory elements (SREs) using literature and experimental datasets.

BRCA1 and BRCA2 whole cDNA analysis in unsolved hereditary breast/ovarian cancer patients.

Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA1/2) explain an important fraction of hereditary breast/ovarian cancer (HBOC) cases. Genetic testing generally involves examining coding regions and exon/intron boundaries, thus the frequency of deleterious variants in non-coding regions is unknown. Here we analysed BRCA1/2 whole cDNA in a large cohort of 320 unsolved high-risk HBOC cases in order to identify potential splicing alterations explained by variants in BRCA1/2 deep intronic regions.

Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes.

BRCA1 and BRCA2 (BRCA1/2) genetic variants that disrupt messenger RNA splicing are commonly associated with increased risks of developing breast/ovarian cancer. The majority of splicing studies published to date rely on qualitative methodologies (i.e.

Alternative transcript imbalance underlying breast cancer susceptibility in a family carrying PALB2 c.3201+5G>T.

Purpose: Disruption of splicing motifs by genetic variants can affect the correct generation of mature mRNA molecules leading to aberrant transcripts. In some cases, variants may alter the physiological transcription profile composed of several transcripts, and an accurate in vitro evaluation is crucial to establish their pathogenicity. In this study, we have characterized a novel PALB2 variant c.

Screening of deep intronic regions by targeted gene sequencing identifies the first germline variant causing pseudoexon activation in a patient with breast/ovarian cancer.

Background: Genetic analysis of and for the diagnosis of hereditary breast and ovarian cancer (HBOC) is commonly restricted to coding regions and exon-intron boundaries. Although germline pathogenic variants in these regions explain about ~20% of HBOC cases, there is still an important fraction that remains undiagnosed. We have screened deep intronic regions to identify potential spliceogenic variants that could explain part of the missing HBOC susceptibility.

Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.

Purpose: Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research.

Methods: We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2).

Comparison of mRNA splicing assay protocols across multiple laboratories: recommendations for best practice in standardized clinical testing.

Background: Accurate evaluation of unclassified sequence variants in cancer predisposition genes is essential for clinical management and depends on a multifactorial analysis of clinical, genetic, pathologic, and bioinformatic variables and assays of transcript length and abundance. The integrity of assay data in turn relies on appropriate assay design, interpretation, and reporting.

Methods: We conducted a multicenter investigation to compare mRNA splicing assay protocols used by members of the ENIGMA (Evidence-Based Network for the Interpretation of Germline Mutant Alleles) consortium.

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants.

RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations.

Mutation analysis of the BCCIP gene for breast cancer susceptibility in breast/ovarian cancer families.

Objective: About 5%-10% of breast cancer is due to inherited disease predisposition. Currently, mutations in the BRCA1 and BRCA2 genes explain less than 25% of the familial clustering of breast cancer, and additional susceptibility genes are suspected. The BCCIP gene plays an important role in the regulation of gene transcription and cell proliferation and could be involved in the maintenance of genomic integrity.

Mutation analysis of the SHFM1 gene in breast/ovarian cancer families.

Purpose: About 5-10 % of breast cancer is due to inherited disease predisposition. Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25 % of familial aggregation of breast cancer, which suggests the involvement of additional genetic susceptibility. The SHFM1 [split hand/foot malformation (ectrodactyly) type 1] gene plays an important role in the regulation of gene transcription and cell proliferation and may be involved in the maintenance of genomic integrity.

Novel BRCA1 deleterious mutation (c.1949_1950delTA) in a woman of Senegalese descent with triple-negative early-onset breast cancer.

Limited information exists regarding BRCA1 and BRCA2 genetic testing and genetic diversity in BRCA1 and BRCA2 in sub-Saharan African populations. We report a novel mutation that consists of a deletion of 2 bp (c.1949_1950delTA) in the exon 11 of the BRCA1 gene.

Identification of a new complex deleterious mutation in exon 18 of the BRCA2 gene in a hereditary male/female breast cancer family.

We report a novel complex mutation that consists of a deletion of 12 bp and an insertion of 2 bp (c.8402_8413del12ins2bp) in the exon 18 of the BRCA2 gene. This is a frameshift mutation that causes a disruption of the translational reading frame resulting in a stop codon downstream in the 2729 position of the BRCA2 protein.