. "25" . "Endogenous processes and exogenous agents cause constant DNA damage. DNA double-strand breaks are among the most serious types of damage. They are mainly repaired by homologous recombination, where the BRCA2 protein plays a dominant role. 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 and prophylactic surgery. Apart from clearly pathogenic mutations, variants leading only to a single amino acid substitution are often identified. Since the influence of these variants on cancer risk is unknown, they represent a major clinical problem. The aim of this paper is to summarize the current possibilities of predicting pathogenicity of BRCA2 variants. In some cases, genetic methods are able to classify variants with high probability; however, their use is often limited by low frequency of the variants or inaccessibility of samples for mRNA isolation or DNA from family members. Alternatively, functional assays performed in various cellular models may be employed. Multiple functional tests and cellular models are presented and characterized, including their advantages and limitations. A new model of human syngeneic cell lines developed by the authors is presented, in which one BRCA2 allele is deleted and the variant is introduced into the other allele by homologous recombination. This model has the potential to evaluate function of variants without some of the unwanted effects of the other models. Currently, this model is being applied to variants identified in patients with hereditary cancer predisposition in the Masaryk Memorial Cancer Institute. Functional assays in cellular models including a new model of syngeneic cell lines described by the authors have a great potential in evaluating clinical importance of unclassified variants in the BRCA2 gene, especially in cases where genetic tests are not applicable."@en . "0862-495X" . . . "9"^^ . "Vlivem vn\u011Bj\u0161\u00EDch a vnit\u0159n\u00EDch faktor\u016F doch\u00E1z\u00ED v bu\u0148ce neust\u00E1le k po\u0161kozov\u00E1n\u00ED DNA. Mezi nejz\u00E1va\u017En\u011Bj\u0161\u00ED pat\u0159\u00ED tvorba dvou\u0159et\u011Bzcov\u00FDch zlom\u016F. Jejich bezchybn\u00E1 oprava se uskute\u010D\u0148uje p\u0159edev\u0161\u00EDm mechanizmem homologn\u00ED rekombinace, v n\u011Bm\u017E jednu z kl\u00ED\u010Dov\u00FDch \u00FAloh hraje protein BRCA2. Vrozen\u00E9 mutace v genu BRCA2 jsou p\u0159\u00ED\u010Dinou vzniku n\u00E1dor\u016F prsu, ovari\u00ED, pankreatu aj. P\u0159\u00EDtomnost patogenn\u00ED mutace v BRCA2 u pacient\u016F \u010Di jejich rodinn\u00FDch p\u0159\u00EDslu\u0161n\u00EDk\u016F je d\u016Fvodem k jejich dispenzarizaci s c\u00EDlem v\u010Das zachytit n\u00E1dorov\u00E9 onemocn\u011Bn\u00ED a je indikac\u00ED k profylaktick\u00FDm chirurgick\u00FDm v\u00FDkon\u016Fm. Vedle zjevn\u011B patogenn\u00EDch mutac\u00ED jsou v genu BRCA2 \u010Dasto zji\u0161\u0165ov\u00E1ny unik\u00E1tn\u00ED bodov\u00E9 varianty vedouc\u00ED pouze k z\u00E1m\u011Bn\u011B jedn\u00E9 aminokyseliny, u kter\u00FDch je obt\u00ED\u017En\u00E9 ur\u010Dit klinick\u00FD v\u00FDznam. C\u00EDlem \u010Dl\u00E1nku je podat p\u0159ehled o sou\u010Dasn\u00FDch mo\u017Enostech hodnocen\u00ED patogenity variant v genu BRCA2. Genetick\u00E9 metody jsou v n\u011Bkter\u00FDch p\u0159\u00EDpadech schopny patogenitu variant s vysokou pravd\u011Bpodobnost\u00ED predikovat, jejich proveden\u00ED je v\u0161ak \u010Dasto limitov\u00E1no n\u00EDzkou frekvenc\u00ED varianty \u010Di nedostupnost\u00ED vzork\u016F pro izolaci mRNA nebo vzork\u016F DNA od rodinn\u00FDch p\u0159\u00EDslu\u0161n\u00EDk\u016F. Alternativou jsou v takov\u00FDch p\u0159\u00EDpadech metody funk\u010Dn\u00EDho hodnocen\u00ED variant prov\u00E1d\u011Bn\u00E9 v r\u016Fzn\u00FDch bun\u011B\u010Dn\u00FDch modelech. D\u00E1le je p\u0159edstaven autory vyvinut\u00FD lidsk\u00FD n\u00E1dorov\u00FD syngenn\u00ED bun\u011B\u010Dn\u00FD model, ve kter\u00E9m je jedna alela BRCA2 genu nefunk\u010Dn\u00ED a do druh\u00E9 je homologn\u00ED rekombinac\u00ED vnesena studovan\u00E1 varianta. Tento model m\u00E1 potenci\u00E1l hodnotit funkci variant s minimem ne\u017E\u00E1douc\u00EDch vliv\u016F jin\u00FDch model\u016F. V sou\u010Dasn\u00E9 dob\u011B je tento model prakticky zkou\u0161en u variant zji\u0161t\u011Bn\u00FDch u pacient\u016F s d\u011Bdi\u010Dnou n\u00E1dorovou predispozic\u00ED v Masarykov\u011B onkologick\u00E9m \u00FAstavu. Funk\u010Dn\u00ED testy v bun\u011B\u010Dn\u00FDch modelech v\u010Detn\u011B autory vyvinut\u00E9ho nov\u00E9ho modelu syngenn\u00EDch bun\u011B\u010Dn\u00FDch lini\u00ED p\u0159edstavuj\u00ED velk\u00FD potenci\u00E1l k ur\u010Den\u00ED patogenity variant s nejasn\u00FDm klinick\u00FDm v\u00FDznamem v BRCA2 genu, p\u0159edev\u0161\u00EDm tam, kde jsou genetick\u00E9 metody neprovediteln\u00E9."@cs . . "P(ED2.1.00/03.0101), P(NS10536)" . . . "2"^^ . . . . . . . "RIV/00209805:_____/12:#0000316!RIV13-MSM-00209805" . . . "Evaluation of variants of unknown significance in the BRCA2 gene"@en . "Hodnocen\u00ED variant nezn\u00E1m\u00E9ho v\u00FDznamu v genu BRCA2" . "Mach\u00E1\u010Dkov\u00E1, Eva" . "6"^^ . "Hodnocen\u00ED variant nezn\u00E1m\u00E9ho v\u00FDznamu v genu BRCA2" . "BRCA2 gene; variants of unknown significance; missense mutation; functional assays"@en . "RIV/00209805:_____/12:#0000316" . "Klinick\u00E1 onkologie" . "Evaluation of variants of unknown significance in the BRCA2 gene"@en . "Foretov\u00E1, Lenka" . "Vlivem vn\u011Bj\u0161\u00EDch a vnit\u0159n\u00EDch faktor\u016F doch\u00E1z\u00ED v bu\u0148ce neust\u00E1le k po\u0161kozov\u00E1n\u00ED DNA. Mezi nejz\u00E1va\u017En\u011Bj\u0161\u00ED pat\u0159\u00ED tvorba dvou\u0159et\u011Bzcov\u00FDch zlom\u016F. Jejich bezchybn\u00E1 oprava se uskute\u010D\u0148uje p\u0159edev\u0161\u00EDm mechanizmem homologn\u00ED rekombinace, v n\u011Bm\u017E jednu z kl\u00ED\u010Dov\u00FDch \u00FAloh hraje protein BRCA2. Vrozen\u00E9 mutace v genu BRCA2 jsou p\u0159\u00ED\u010Dinou vzniku n\u00E1dor\u016F prsu, ovari\u00ED, pankreatu aj. P\u0159\u00EDtomnost patogenn\u00ED mutace v BRCA2 u pacient\u016F \u010Di jejich rodinn\u00FDch p\u0159\u00EDslu\u0161n\u00EDk\u016F je d\u016Fvodem k jejich dispenzarizaci s c\u00EDlem v\u010Das zachytit n\u00E1dorov\u00E9 onemocn\u011Bn\u00ED a je indikac\u00ED k profylaktick\u00FDm chirurgick\u00FDm v\u00FDkon\u016Fm. Vedle zjevn\u011B patogenn\u00EDch mutac\u00ED jsou v genu BRCA2 \u010Dasto zji\u0161\u0165ov\u00E1ny unik\u00E1tn\u00ED bodov\u00E9 varianty vedouc\u00ED pouze k z\u00E1m\u011Bn\u011B jedn\u00E9 aminokyseliny, u kter\u00FDch je obt\u00ED\u017En\u00E9 ur\u010Dit klinick\u00FD v\u00FDznam. C\u00EDlem \u010Dl\u00E1nku je podat p\u0159ehled o sou\u010Dasn\u00FDch mo\u017Enostech hodnocen\u00ED patogenity variant v genu BRCA2. Genetick\u00E9 metody jsou v n\u011Bkter\u00FDch p\u0159\u00EDpadech schopny patogenitu variant s vysokou pravd\u011Bpodobnost\u00ED predikovat, jejich proveden\u00ED je v\u0161ak \u010Dasto limitov\u00E1no n\u00EDzkou frekvenc\u00ED varianty \u010Di nedostupnost\u00ED vzork\u016F pro izolaci mRNA nebo vzork\u016F DNA od rodinn\u00FDch p\u0159\u00EDslu\u0161n\u00EDk\u016F. Alternativou jsou v takov\u00FDch p\u0159\u00EDpadech metody funk\u010Dn\u00EDho hodnocen\u00ED variant prov\u00E1d\u011Bn\u00E9 v r\u016Fzn\u00FDch bun\u011B\u010Dn\u00FDch modelech. D\u00E1le je p\u0159edstaven autory vyvinut\u00FD lidsk\u00FD n\u00E1dorov\u00FD syngenn\u00ED bun\u011B\u010Dn\u00FD model, ve kter\u00E9m je jedna alela BRCA2 genu nefunk\u010Dn\u00ED a do druh\u00E9 je homologn\u00ED rekombinac\u00ED vnesena studovan\u00E1 varianta. Tento model m\u00E1 potenci\u00E1l hodnotit funkci variant s minimem ne\u017E\u00E1douc\u00EDch vliv\u016F jin\u00FDch model\u016F. V sou\u010Dasn\u00E9 dob\u011B je tento model prakticky zkou\u0161en u variant zji\u0161t\u011Bn\u00FDch u pacient\u016F s d\u011Bdi\u010Dnou n\u00E1dorovou predispozic\u00ED v Masarykov\u011B onkologick\u00E9m \u00FAstavu. Funk\u010Dn\u00ED testy v bun\u011B\u010Dn\u00FDch modelech v\u010Detn\u011B autory vyvinut\u00E9ho nov\u00E9ho modelu syngenn\u00EDch bun\u011B\u010Dn\u00FDch lini\u00ED p\u0159edstavuj\u00ED velk\u00FD potenci\u00E1l k ur\u010Den\u00ED patogenity variant s nejasn\u00FDm klinick\u00FDm v\u00FDznamem v BRCA2 genu, p\u0159edev\u0161\u00EDm tam, kde jsou genetick\u00E9 metody neprovediteln\u00E9." . "[DD7BC8E73801]" . "http://www.linkos.cz/files/klinicka-onkologie/172/4076.pdf" . "Hodnocen\u00ED variant nezn\u00E1m\u00E9ho v\u00FDznamu v genu BRCA2"@cs . "Hodnocen\u00ED variant nezn\u00E1m\u00E9ho v\u00FDznamu v genu BRCA2"@cs . "Hucl, Tom\u00E1\u0161" . "supplementum" . . . "139455" . . . "CZ - \u010Cesk\u00E1 republika" .