RT Journal Article
SR Electronic
T1 Clinical impact of unclassified variants of the <em>BRCA1</em> and <em>BRCA2</em> genes
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 783
OP 786
DO 10.1136/jmedgenet-2011-100305
VO 48
IS 11
A1 Mohammad R Akbari
A1 Shiyu Zhang
A1 Isabel Fan
A1 Robert Royer
A1 Song Li
A1 Harvey Risch
A1 John McLaughlin
A1 Barry Rosen
A1 Ping Sun
A1 Steven A Narod
YR 2011
UL http://jmg.bmj.com/content/48/11/783.abstract
AB Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p&lt;10−4). In contrast, the cumulative risk of cancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.