Gene selection

NGS analysis of hereditary cancer susceptibility genes was performed using two different gene panels. The genes analyzed were selected based on their association to hereditary cancer predisposition. In the majority of cancer syndromes the mode of inheritance is dominant. Thus, a single pathogenic variant in heterozygosity in one of these genes may be the causative reason of cancer predisposition. Several of these genes also have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions. BRCA2, BRIP1, PALB2, and RAD51C are associated with Fanconi anemia. ATM and MRE11A are associated with ataxia-telangiectasia and ataxia-telangiectasia-like disorder (ATLD), respectively. MLH1, MSH2, PMS2, and MSH6 are associated with constitutional mismatch repair deficiency (CMMR-D). MUTYH is associated with MUTYH-associated polyposis (MAP). NBN and RAD50 are associated with Nijmegen breakage syndrome and Nijmegen breakage syndrome-like disorder (NBSLD), respectively. The majority of patients who required hereditary cancer testing had a personal or family history of Breast and/or Ovarian cancer and therefore, the vast majority of genes analyzed in this study are associated with increased risk of Breast and/or Ovarian cancer. In addition, the genes were further classified as high, moderate/intermediate or low penetrance genes based on their relative risk for cancer development that they confer to pathogenic variant carriers. High penetrance (or high risk) genes are considered those which when mutated, confer a high Relative Risk of cancer development (greater than 4 times the risk of the general population). Moreover, they are included in guidelines for cancer predisposition testing and specific clinical management recommendations for patients carrying pathogenic variants have been formulated by large working groups [5–7]. Pathogenic variants in moderate penetrance (or moderate risk) genes confer a 2–4 times risk of cancer development compared to the general population. Low penetrance/risk genes are those related to less than 2 times risk of cancer or those with limited or yet insufficient data available concerning their association and magnitude of cancer risk. Although this categorization is constantly altered in reflection to the accumulated clinical information, based on the latest published data [3, 5–10], the genes analyzed are summarized in Table 1.

List of Genes analyzed by the Hereditary Cancer panels and their association with various cancer types and syndromes

Familial Atypical Multiple Mole Melanoma Syndrome,

Melanoma-Pancreatic Cancer Syndrome

^a BRCA1, BRCA2, CDH1, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2, NBN, RAD51C, RAD51D, BARD1, BLM, ABRAXAS1, MRE11, RAD50, XRCC2 were included in the first version of the HerediGENE panel (26 gene panel) whereas APC, BMPR1A, BRCA1, BRCA2, CDH1, CDK4, CDKN2A, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, PTEN, RET, SMAD4, STK11, TP53, VHL, ATM, BRIP1, CHEK2, NBN, RAD51C, RAD51D, BARD1, CHEK1, MRE11, NF1, RAD50, RAD51B were included in the second version of the HerediGENE panel (33 gene panel)