Abstract
We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.
Highlights
We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes
Next-generation sequencing (NGS) studies have reported that as many as ~18% of patients diagnosed with colorectal cancer (CRC) < age of 50 years have pathogenic germline variants in genes that are not traditionally associated with CRC, including ATM, CHEK2, BRCA1, BRCA2, CDKN2A or PALB27,8, while up to 15% of hereditary breast and ovarian cancer (HBOC) patients harbor pathogenic variants in known breast cancer (BC) predisposing genes, including RAD51C, RAD51D, ATM, CHEK2, BRIP1, PALB2, BARD1, RECQL, TP53, CDH1 and NBN9,10
We identified 9 cases (5% of 191) who carried 9 pathogenic or likely pathogenic variants that were confirmed by cycling temperature capillary electrophoresis, showing 100% concordance (Fig. 1, Table 1)
Summary
We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). More than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice. Highly-penetrant pathogenic germline variants that explain familial aggregation and/or an early-onset of the disease (e.g. pathogenic variants in APC and DNA mismatch repair (MMR) genes) are detected in only 5–10% of the cases[5]. In hereditary breast and ovarian cancer (HBOC), up to ~25% of the cases can be explained by the highly penetrant risk genes BRCA1 and BRCA26. Regarding BRCA1 and BRCA2 genes, up to 20% of all variants are still being classified as VUS19, while about one-fifth to one-third are classified in the case of the DNA MMR gene variants[20]
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