title: Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers.
abstract: CHEK2 mutations are associated with increased cancer risks, including breast; however, published risk estimates are limited to those conferred by CHEK2 founder mutations, presenting uncertainty in risk assessment for carriers of other CHEK2 mutations. This study aimed to assess phenotypes and molecular characteristics of CHEK2 mutation carriers (CHEK2 + s) from a multi-gene panel testing (MGPT) cohort, focusing on comparing phenotypes of founder and non-founder CHEK2 + s. Clinical histories and molecular results were reviewed from 45,879 patients who underwent MGPT including CHEK2 at a commercial laboratory. Of individuals tested, 2.4% (n = 1085) were CHEK2 + s. Sixteen individuals harbored biallelic CHEK2 mutations, bringing the total number of CHEK2 mutations detected in this cohort to 1101. Personal/family cancer histories were compared between founder (n = 576; included c.1100delC, p.S428F, c.444 + 1G > A, and EX8_9del) and non-founder (n = 259) CHEK2 + s using Fisher's exact test and multivariate logistic regression analysis. Individuals carrying the p.I157T moderate risk founder mutation (n = 231), additional mutations in non-CHEK2 genes (n = 83), or biallelic mutations (n = 16) were excluded from phenotype analysis, as were cases with no clinical information provided. No significant phenotypic differences were observed between founder and non-founder CHEK2 + s. These data suggest that cancer risks reported for founder mutations may be generalizable to all CHEK2 + s, particularly for breast cancer.
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA. Electronic address: tleedom@ambrygen.com.
authors.forename: Tracey P
authors.initials: TP
authors.lastname: Leedom
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: LaDuca
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA.
authors.forename: Shuwei
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Dolinsky
authors.affiliation: Department of Clinical Diagnostics, Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656, USA; Department of Pediatrics, Division of Genetics and Genomic Medicine, University of California, 2054 E. Hewitt Hall, Irvine, CA 92697, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Chao
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006801:Humans
chemical_list: D064447:Checkpoint Kinase 2
keywords: CHEK2; Hereditary breast cancer; breast cancer; cancer risk; founder mutation