The RAD51C exonic splice-site mutations c.404G>C and c.404G>T are associated with familial breast and ovarian cancer.
Whereas RAD51C mutations increase the relative risk for ovarian cancer (OC) to 5.88 (95% confidence interval=2.91-11.88, P=7.65×10), the associated risks for breast cancer (BC) remain largely unknown, as deleterious RAD51C alterations are extremely rare in BC-only families. Here, we report the results of a RAD51C mutational screening in a large series of German familial index patients negative for pathogenic BRCA1/2 mutations and the in-vitro characterization of two novel exonic RAD51C splice-site mutations. A total of 610 index cases derived from BC/OC (n=587) or OC-only families (n=23) were screened for potentially deleterious germline mutations in RAD51C. The frequencies of two splice-site mutations were assessed by single-nucleotide polymorphism genotyping in 1410 additional cases not enriched for OC family history. In three independent families, we identified novel splice-site mutations affecting the last nucleotide of exon 2 (c.404G>C, c.404G>T). Both mutations disrupt proper RAD51C pre-mRNA processing and cause a missense substitution immediately followed by a stop codon (p.Cys135Serfs*2; p.Cys135Leufs*2). Even though both mutations have similar effects on the protein level, they are associated with either BC/OC, OC-only, or BC-only family histories. The rare finding of a clearly truncating RAD51C mutation in an early-onset BC patient with a BC-only family history supports the notion that compromised RAD51C function may result in both BC and OC. Large international collaborative studies are needed to quantify the relative risk of RAD51C alterations for BC and to unravel the genetic modifying factors that determine phenotypic variability with respect to cancer site.
aCenter for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty bCenter for Molecular Medicine Cologne (CMMC) cCologne Center for Genomics dInstitute for Human Genetics eCologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne fDepartment of Gynecology and Obstetrics, University Clinics of Münster, Münster gDepartment of Genomics, Life & Brain Center, University of Bonn, Bonn hDepartment of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany.
Guido
G
Neidhardt
Alexandra
A
Becker
Jan
J
Hauke
Judit
J
Horváth
Nadja
N
Bogdanova Markov
Stefanie
S
Heilmann-Heimbach
Heide
H
Hellebrand
Holger
H
Thiele
Janine
J
Altmüller
Peter
P
Nürnberg
Alfons
A
Meindl
Kerstin
K
Rhiem
Britta
B
Blümcke
Barbara
B
Wappenschmidt
Rita K
RK
Schmutzler
Eric
E
Hahnen
D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree
D004268:DNA-Binding Proteins; C448305:RAD51C protein, human