Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study

Anikó Bozsik; János Papp; Vince Kornél Grolmusz; Attila Patócs; Edit Oláh; Henriett Butz

doi:10.4143/crt.2021.1078

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자료유형: 학술저널

저자정보: Anikó Bozsik (National Institute of Oncology Budapest Hungary) János Papp (National Institute of Oncology Budapest Hungary) Vince Kornél Grolmusz (National Institute of Oncology Budapest Hungary) Attila Patócs (National Institute of Oncology Budapest Hungary) Edit Oláh (National Institute of Oncology Budapest Hungary) Henriett Butz (National Institute of Oncology Budapest Hungary)

저널정보: 대한암학회 Cancer Research and Treatment Cancer Research and Treatment 제54권 제4호

발행연도: 2022.10

수록면: 970 - 984 (15page)

DOI: 10.4143/crt.2021.1078

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Purpose While BRCA1/2 genes are commonly investigated, variants of unknown significance (VUS) and variants with potential splice effect are still being detected and they represent a substantial challenge in genetic counseling and therapy. Materials and Methods Out of genetically tested 3,568 hereditary breast and ovarian cancer probands five, functionally not investigated variants with potential splice-modifying effect were subjected to functional characterization. Transcript-level analysis on peripheral blood-derived RNA of the carriers was performed to test aberrant splicing. The completeness of the aberrant splicing event was also studied, existence and extent of nonsense-mediated decay was even addressed. Clinical and phenotype data, pedigree and co-segregation analyses were also done. Locus-specific loss of heterozygosity (LOH) in tumor tissues was additionally tested. Results In case of the BRCA1:c.4484+4dupA and the BRCA1:c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1:c.4358-31A>C, by producing incomplete aberrant splicing, was highlighted as strong VUS, but in lack of other supporting evidence, re-categorization was not possible. The likely pathogenic assertion of previously not reported BRCA2:c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2:c.793G>A failed to present aberrant splicing in spite of suggestive predictions, which altered its original VUS evaluation into likely benign class. Conclusion We presented molecular and clinical evidence for reclassification of four out of five BRCA1/2 variants. Both up- and down-classification harbour important clinical significance. Patients carrying re-classified pathogenic variants in the future will not be dropped out from medical surveillance, preventive measures, treatment and predictive family screening in relatives at risk.

#BRCA1 #BRCA2 #Breast neoplasms #Reclassification #Variants of unknown significance #Splicing

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