Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations Ovarian Cancer and Us OVARIAN CANCER and US Ovarian Cancer and Us

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Tuesday, March 29, 2016

Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations



pdf
  In the present study, we have sequenced 13 additional genes that
have been deemed HBOC susceptibility loci (BARD1, EPCAM,
MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PMS2, PTEN,
RAD51B, STK11, and XRCC2 [Minion et al., 2015]). These genes
encode proteins with roles in DNA repair, surveillance, and cell
cycle regulation (Fig. 1; for further evidence supporting this gene
set see Supp. Table S1 [Apostolou and Fostira, 2013; Al Bakir and
Gabra, 2014]), and are associated with specific disease syndromes
that confer an increased risk of BC and OC, as well as many other
types of cancer (Supp. Table S2).
 EPCAM, MLH1, MSH2, MSH6, and PMS2 have also been
proposed to harbor high-risk BC alleles, but the RR (relative risk) is still controversial
[Maxwell and Domchek, 2013].

 ABSTRACT: 
BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding 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 and prioritize noncoding variants of uncertain significance in regulatory,
coding, and intronic regions based on changes in binding sites in these genes. .........When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and cosegregation analysis.
Hum Mutat 00:1–13, 2016

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