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Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2
Author(s) -
Kraus Cornelia,
Hoyer Juliane,
Vasileiou Georgia,
Wunderle Marius,
Lux Michael P.,
Fasching Peter A.,
Krumbiegel Mandy,
Uebe Steffen,
Reuter Miriam,
Beckmann Matthias W.,
Reis André
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30428
Subject(s) - palb2 , chek2 , penetrance , msh6 , msh2 , mlh1 , genetics , biology , genetic testing , breast cancer , ovarian cancer , mutation , cancer , gene , germline mutation , dna mismatch repair , colorectal cancer , phenotype
Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high‐ and moderate to low‐penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel‐based screening of 14 BC/OC susceptibility genes ( BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2 ) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple‐negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2 . To further characterize mutations located in or nearby splicing consensus sites we performed RT‐PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2 , we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2 . Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide‐spread testing will help improve penetrance assessment of variants in these risk genes.