Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F19%3A00077984" target="_blank" >RIV/00023001:_____/19:00077984 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00209805:_____/19:00078130
Výsledek na webu
<a href="https://www.tandfonline.com/doi/abs/10.1080/15384047.2018.1550566?journalCode=kcbt20" target="_blank" >https://www.tandfonline.com/doi/abs/10.1080/15384047.2018.1550566?journalCode=kcbt20</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1080/15384047.2018.1550566" target="_blank" >10.1080/15384047.2018.1550566</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing
Popis výsledku v původním jazyce
Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance or prophylactic surgery. Besides clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. The influence of such variants on cancer risk is often unknown, making their presence a major clinical problem. When genetic methods are insufficient to classify these variants, functional assays with various cellular models are performed. We developed and applied a new syngeneic model of human cancer cells to test all variants of unknown significance in exon 18 identified by genetic testing of high-risk cancer patients in the Czech Republic, via introduction of constructs containing each of these variants into the wild-type allele of BRCA2-heterozygous DLD1 cells (BRCA2(wt/Delta ex11)). We found unaffected DNA repair function of BRCA2 in cell lines BRCA2(7997G>C/Delta ex11), BRCA2(8111C>T/Delta ex11), BRCA2(8149G>T/Delta ex11), BRCA2(8182G>A/Delta ex11), and BRCA2(8182G>T/Delta ex11), whereas the cell line BRCA2(8168A>G/Delta ex11) and the nonsense mutation carrying line BRCA2(8305G>T/Delta ex11) did affect protein function. Targeting the BRCA2 wild-type allele with a construct carrying the variant c.7988A> G resulted in incorporation exclusively into the already defective allele in all viable clones, strongly suggesting a detrimental phenotype. Our model thus offers a valuable tool for the functional evaluation of unclassified variants in the BRCA2 gene and provides a stable and distributable cellular resource for further research.
Název v anglickém jazyce
Functional evaluation of variants of unknown significance in the BRCA2 gene identified in genetic testing
Popis výsledku anglicky
Heterozygous germline BRCA2 mutations predispose to breast, ovarian, pancreatic and other types of cancer. The presence of a pathogenic mutation in patients or their family members warrants close surveillance or prophylactic surgery. Besides clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. The influence of such variants on cancer risk is often unknown, making their presence a major clinical problem. When genetic methods are insufficient to classify these variants, functional assays with various cellular models are performed. We developed and applied a new syngeneic model of human cancer cells to test all variants of unknown significance in exon 18 identified by genetic testing of high-risk cancer patients in the Czech Republic, via introduction of constructs containing each of these variants into the wild-type allele of BRCA2-heterozygous DLD1 cells (BRCA2(wt/Delta ex11)). We found unaffected DNA repair function of BRCA2 in cell lines BRCA2(7997G>C/Delta ex11), BRCA2(8111C>T/Delta ex11), BRCA2(8149G>T/Delta ex11), BRCA2(8182G>A/Delta ex11), and BRCA2(8182G>T/Delta ex11), whereas the cell line BRCA2(8168A>G/Delta ex11) and the nonsense mutation carrying line BRCA2(8305G>T/Delta ex11) did affect protein function. Targeting the BRCA2 wild-type allele with a construct carrying the variant c.7988A> G resulted in incorporation exclusively into the already defective allele in all viable clones, strongly suggesting a detrimental phenotype. Our model thus offers a valuable tool for the functional evaluation of unclassified variants in the BRCA2 gene and provides a stable and distributable cellular resource for further research.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30101 - Human genetics
Návaznosti výsledku
Projekt
<a href="/cs/project/NS10536" target="_blank" >NS10536: Nová metoda funkčního hodnocení variant v BRCA2 genu</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2019
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Cancer Biology and Therapy
ISSN
1538-4047
e-ISSN
—
Svazek periodika
20
Číslo periodika v rámci svazku
5
Stát vydavatele periodika
US - Spojené státy americké
Počet stran výsledku
9
Strana od-do
633-641
Kód UT WoS článku
000465170300006
EID výsledku v databázi Scopus
2-s2.0-85060025448