Feb 9, 2016

Prioritizing variants in complete Hereditary Breast and Ovarian Cancer (HBOC) genes in patients lacking known BRCA mutations

BioRxiv : the Preprint Server for Biology
Natasha G CaminskyPeter K Rogan


BRCA1 and BRCA2 testing for HBOC does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N=287), including non-coding and flanking sequences of ATM , BARD1 , BRCA1 , BRCA2 , CDH1 , CHEK2 , EPCAM , MLH1 , MRE11A , MSH2 , MSH6 , MUTYH , NBN , PALB2 , PMS2 , PTEN , RAD51B , STK11 , TP53 , and XRCC2 , identified 38,372 unique variants. We apply information theory (IT) to predict novel functions for and prioritize non-coding variants of uncertain significance (VUS) in throughout regulatory, coding, and intronic regions based on changes in binding sites in these genesof these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes inin transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) protein binding sites following mutationat mutated binding sites. We prioritized variants affecting the strengths of 10 variants affecting splice sites (4 natural, 6 cryptic), 148 SRBS, 36 TFBS, and 31 RBBS binding strength-affecting variantss. Three variants were also prioritized based on their predicted effects on mRNA secondary (2°) structure, and 17 for pseudoexon activation. Additionally, 4 frames...Continue Reading

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Mentioned in this Paper

TP53 gene
BRCA2 Protein
BRCA1 protein, human
CFC1 gene
XRCC2 gene
CHEK2 gene
Pathogenic Organism
MSH2 gene

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