Preliminary molecular evidence associating a novel BRCA1 synonymous variant with hereditary ovarian cancer syndrome

Minucci, Angelo; Concolino, Paola; Bonis, Maria De; Costella, Alessandra; Paris, Ida; Scambia, Giovanni; Capoluongo, Ettore

doi:10.1038/s41439-018-0003-0

Cited by 4 publications

(2 citation statements)

References 8 publications

(8 reference statements)

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“…The misinterpretation of a VUS has the potential to lead to mismanagement of both the patients and their relatives. For this reason, many efforts should be spent to classify correctly a VUS as deleterious variant rather than as a benign polymorphism [5,6,7]. Currently, to aid genetic counseling of subjects carrying a BRCA1/2 VUSs, both genetic and functional molecular methods (in-silico and through experimental procedures) are used for the classification of new variants.…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and BRCA2 Testing through Next Generation Sequencing in a Small Cohort of Italian Breast/Ovarian Cancer Patients: Novel Pathogenic and Unknown Clinical Significance Variants

Concolino

Gelli

Rizza

et al. 2019

IJMS

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The aim of this report is to describe results of BRCA1 and BRCA2 Next Generation Sequencing Analysis (NGS) analysis in 132 selected Italian patients with breast/ovarian cancer. A NGS pipeline with a reliable Copy Number Variation (CNV) prediction algorithm was applied. In addition, VarSome and Priors V2.0 Software were employed for in silico analysis of novel missense variants. A total of 37 BRCA1 and BRCA2 pathogenic variants were found in 34 unrelated subjects with a frequency of positive patients of 25.7% (34/132). Twenty-four deleterious variants were detected in BRCA1 (representing the 64.9% of all identified pathogenic defects) and thirteen (35.1% of all identified pathogenic variants) in BRCA2 gene. The percentage of patients carrying a variant of unknown significance (VUS) was 7.5% (10/132). In addition, seven novel variants (five in BRCA2 and two in BRCA1 gene), never previously reported, were identified. Our approach represents a robust and easy-to-use method for full BRCA1/2 screening. However, a consistent number of our high-risk families still remained without a satisfying answer. Necessarily, further collective efforts must be directed to a definitive classification of VUSs. The future auspice is that the use of multi-gene panel and more advanced screenings, such as whole exome sequencing and/or RNA seq, in routine diagnostics increases the detection rate.

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Section: Introductionmentioning

confidence: 99%

BRCA1 and BRCA2 Testing through Next Generation Sequencing in a Small Cohort of Italian Breast/Ovarian Cancer Patients: Novel Pathogenic and Unknown Clinical Significance Variants

Concolino

Gelli

Rizza

et al. 2019

IJMS

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“…HOCS is associated with mutations in germ cell-associated susceptibility genes, and the penetrance rate is high. Detection of related gene mutations has become an effective means of screening for high-risk HOCS populations [4]. Current research confirms that breast cancer susceptibility gene 1/2 (BRCA1/2) is the most important susceptibility gene associated with HOCS [5,6].…”

Section: Introductionmentioning

confidence: 99%

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

Liao

Song

et al. 2020

J Assist Reprod Genet

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Objective Breast cancer susceptibility gene 1/2 (BRCA1/2) is the most important susceptibility gene associated with hereditary ovarian cancer (HOC). We aimed to screen BRAC1 and BRAC2 gene mutations in a member of a hereditary ovarian cancer family in China, and to analyze the structure and function of the mutant protein. Methods A typical HOC family was selected. Blood samples and pathological tissue samples were taken from the female members of the family. Blood samples from two patients with sporadic ovaries of the same pathological type were taken as a control group. After RNA extraction, PCR amplification was applied and the PCR products were directly sequenced and aligned, prediction and analysis of protein structure and molecular conformation that may be caused by BRCA1/2 mutation. Results The whole gene analysis of BRCA1 and BRCA2 in ovarian cancer patients in the family showed that there were 8 mutations in BRCA1 whole gene sequencing, including 3 nonsense mutations (2314C>T, 2543T>C, 4540T>C); two mutations have been recorded, which are associated with cervical cancer (2844C>T) and endometriosis (3345A>G); three newly discovered mutations (3780A>G, 5069A>G, 3326A>T). Among them, 3780A>G and 5069A>G caused amino acid changes, while 3326A>T mutation caused Arg mutation to stop codon. A total of 7 mutations were detected in BRCA2 whole-genome sequencing, including 5 non-significant mutations (3623A>G, 4034T>C, 4790A>G, 6740G>C, 7469A>G); one no-record mutation (1716T>A), and 1 recorded mutation (1342A>C), which was associated with breast cancer and ovarian cancer. BRCA1 (3326A>T) and BRCA2 (1342A>C) mutations were co-existing in patients (II1, II3, and II5) identified as serous adenocarcinoma grade II. Two cases of ovarian serous cystadenocarcinoma with no history of family tumors were normalized for BRCA1/2 gene sequencing. In the gene detection of III generation female, four females with BRCA2 (1342A>C) mutation were found, and one of them also carried the BRCA1 (3326A>T) mutation, who can be considered a high-risk group of HOC in this family. Online protein structure predictions revealed that BRCA1 (3326A>T) mutations mutated AGA at this site to TGA resulting in a translated Arg (arginine) mutation as a stop codon, while BRCA2 (1342A>C) mutated AAT at this site to CAT resulting in a translated Asn mutation to His. Conclusion The BRCA1 (3326A>T) and BRCA2 (1342A>C) were detected in the HOC family, which may be the susceptibility gene of the family's HOC. The BRCA1/2 gene screening may be possible to obtain high-risk populations in this family.

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SNPs Ability to Influence Disease Risk: Breaking the Silence on Synonymous Mutations in Cancer

Herreros

Janssens

Pepe

et al. 2022

Single Nucleotide Polymorphisms

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Cancer arises when normal cells are transformed into malignant cells by acquiring a number of hallmarks such as sustained proliferative signaling; evading cell death, growth suppression and immune destruction; replicative immortality; and activation of invasion and metastasis (Hanahan et al. 2000, 2011). Sequential accumulation of genetic mutations is a major cause of acquiring these cancer hallmarks in the cell transformation process, and hence a complete characterization of the landscape of pathogenic somatic and congenital mutations in cancer cells forms a holy grail to fully understand cancer biology. Indeed, a lot of effort has gone towards characterizing somatic missense and nonsense single nucleotide variants in the protein coding regions of the genome that result in amino acid substitutions, small insertions and deletions, or a premature STOP codon in the encoded protein. Synonymous mutations on the other hand, nucleotide changes that do not result in an amino acid change in the protein for which they encode, have previously attracted significantly less at attention as candidate cancer driver mutations. However, in a variety of other diseases such as cystic fibrosis, ataxia telangiectasia and even in hereditary cancer syndromes, a causative role for synonymous mutations in disease pathogenesis has been described (Sauna et al. 2011). In addition, the number of synonymous mutations that have a significant impact on the corresponding RNA and protein expression level or isoform in different cancer types is rapidly rising. It is thus becoming clear that there might be a significant fraction of synonymous mutations that are not as ‘silent’ as they have long been considered to be. In this chapter, we will discuss why synonymous mutations have received little attention in the context of cancer. Furthermore, we will describe the recent progress that was made in characterizing the landscape of oncogenic synonymous mutations as well as the variety of molecular mechanisms by which synonymous mutations affect RNA and protein expression levels of oncogenes and tumor suppressors.

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Preliminary molecular evidence associating a novel BRCA1 synonymous variant with hereditary ovarian cancer syndrome

Cited by 4 publications

References 8 publications

BRCA1 and BRCA2 Testing through Next Generation Sequencing in a Small Cohort of Italian Breast/Ovarian Cancer Patients: Novel Pathogenic and Unknown Clinical Significance Variants

BRCA1 and BRCA2 Testing through Next Generation Sequencing in a Small Cohort of Italian Breast/Ovarian Cancer Patients: Novel Pathogenic and Unknown Clinical Significance Variants

Case report: Analysis of BRCA1 and BRCA2 gene mutations in a hereditary ovarian cancer family

SNPs Ability to Influence Disease Risk: Breaking the Silence on Synonymous Mutations in Cancer

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