rs176026

rs176026, also known as c.982A>G, p.Ala328Thr or A328T, represents a common variant in the MAGEC3 gene located on the X-chromosome. Exome sequencing of 159 BRCA-negative Caucasian women identified as being within 3,500 grandmother/granddaughter pairs listed in the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute led to the conclusion that the rs176026(G) allele, at least in Caucasian women, may significantly (~1.4x - 2.8x) increase the risk for ovarian cancer and when present in such patients, may be associated with an earlier age of onset (by about six years). Whether rs176026 is causative or is linked to a causative variant elsewhere in the region is not known. The authors focus on grandmother/granddaughter pairs to help explain 'Stratton's paradox': why are sisters of a woman with ovarian cancer at significantly higher risk of disease than their mother? Their hypothesis rests on X-linked transmission. Specifically, they postulate that a significant fraction of BRCA-negative ovarian cancer cases involve a grandmother at higher risk for ovarian cancer due to a variant on one of her X chromosomes, who 50% of the time passes that variant on to a son who then has a higher risk for prostate cancer, and that son then passes on to all his daughters the X chromosome carrying the variant. The authors note that while the rs176026(G) allele is the less common allele in Caucasians (and Hispanics), it is the major allele in some other populations (notably Africans and some Asian populations). The registry patients studied were nearly all Caucasian; ovarian cancer incidence was reported to be (somewhat) correlated to rs176026(G) allele frequency.

A;G

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G;G

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