Highlights
- •The utility of panel testing in patients with prior single gene testing is unclear.
- •Rescreening of 127 patients identified nine patients with pathogenic mutations.
- •Rescreening identified 53 patients with VUS not identified on prior screening.
- •The clinical implications of VUS, a common finding, remain unknown.
Abstract
Objective
The availability of next-generation sequencing and identification of multiple cancer-related
genes has caused a shift away from single gene testing towards multi-gene panel testing
for hereditary cancer syndromes. However, the utility of panels in individuals who
previously underwent non-informative genetic screening has yet to be evaluated. We
aim to evaluate the use of rescreening and results of multi-gene panels in this rescreened
population.
Methods
We reviewed the medical records for patients who had previously undergone genetic
testing and then underwent multi-gene panel testing at a single institution between
9/2013 and 11/2014.
Results
One hundred and twenty-seven patients with prior genetic testing underwent multi-gene
panels. One hundred and four patients (82%) had a history of cancer and 118 (93%)
had at least one family member with cancer. On primary testing, no pathogenic mutations
were detected and 10 patients (8%) were found to have variants of uncertain significance
(VUS). On repeat multi-gene panel testing, nine patients (7%) were found to have a
pathogenic mutation and 53 patients (42%) were VUS not identified on prior testing.
Conclusions
Seven percent of patients with non-informative primary testing were found to have
a pathogenic mutation with multi-gene panels, suggesting that there is a potential
benefit to be gained from rescreening. However, 42% of patients were found to have
new VUS with panels, a result that can cause patients anxiety without clear clinical
implications.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Gynecologic OncologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Panel testing for inherited susceptibility to breast, ovarian, and colorectal cancer.Genet. Med. 2014; 16: 827-829
- Two decades beyond BRCA1/2: homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy.Gynecol. Oncol. 2015; 137: 343-350
- Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2.Gynecol. Oncol. 2015; 137: 86-92
- Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 18032-18037
- Hereditary ovarian cancer: beyond the usual suspects.Gynecol. Oncol. 2012; 124: 347-353
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet. Med. 2015; 17: 405-423
- A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Science. 1994; 266: 66-71
- Identification of the breast cancer susceptibility gene BRCA2.Nature. 1995; 378: 789-792
- Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies.Am. J. Hum. Genet. 2003; 72: 1117-1130
- BRCA mutation frequency and patterns of treatment response in BRCA mutation–positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.J. Clin. Oncol. 2012; 30: 2654-2663
- Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.J. Clin. Oncol. 2015; 33: 304-311
- Mutations in BRIP1 confer high risk of ovarian cancer.Nat. Genet. 2011; 43: 1104-1107
- Germline mutations in RAD51D confer susceptibility to ovarian cancer.Nat. Genet. 2011; 43: 879-882
- Loss of function germline mutations in RAD51D in women with ovarian carcinoma.Gynecol. Oncol. 2012; 127: 552-555
- Cancer risks in A-T heterozygotes.Int. J. Radiat. Biol. 1994; 66: S177-S182
- Cancer risks and mortality in heterozygous ATM mutation carriers.J. Natl. Cancer Inst. 2005; 97: 813-822
- Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer.Gastroenterology. 2014; 146 (e1-5): 1208-1211
- MutYH mutation carriers have increased breast cancer risk.Cancer. 2012; 118: 1989-1993
- The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast–ovarian cancer kindreds.Cancer Res. 1997; 57: 5480-5484
- Genetic testing and cancer risk management recommendations by physicians for at-risk relatives.Genet. Med. 2011; 13: 148-154
- A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history.Breast Cancer Res. 2009; 11: R8
- Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.J. Genet. Couns. 2007; 16: 241-260
- A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes.Clin. Genet. 2014; 86: 229-237
Article info
Publication history
Published online: August 18, 2015
Accepted:
August 14,
2015
Received in revised form:
August 11,
2015
Received:
April 7,
2015
Footnotes
☆There are no funding sources for this work.
☆☆There are no financial disclosures or other conflicts of interest for any authors.
★The study has been presented as an oral presentation at the Society of Gynecologic Oncology Early Education Summit in December 2014 and was presented as a featured poster at the Society of Gynecologic Oncology Annual Meeting in March 2015 and the American Society of Clinical Oncology Annual Meeting in June 2015.
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
