Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.
Cancer Res Treat
; 54(4): 970-984, 2022 Oct.
Article
in En
| MEDLINE
| ID: mdl-35167739
ABSTRACT
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 ANDMETHODS:
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 BRCA1c.4484+4dupA and the BRCA1c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1c.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 BRCA2c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2c.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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ovarian Neoplasms
/
Breast Neoplasms
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Cancer Res Treat
Year:
2022
Document type:
Article
Affiliation country:
Hungria