A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

遗传诊断有助于对有风险的亲属进行个性化的癌症治疗和临床护理，但是，尽管大肠癌病例中有25％是家族性的，但约有95％的家庭在遗传上尚未解决。在这项研究中，我们对32个已建立的或候选的结直肠癌易感基因的生殖系DNA进行了基因组分析，这些基因来自149个结直肠癌蓄积家庭或仅一例散发性极早发结直肠癌（≤40岁）的家庭诊断时）。我们在10.1％的基因参与者中发现了致病或可能致病的遗传变异，例如装甲运兵车， 极， MSH2 要么 PMS2。的MSH2变体c.2168C> T，p。（Ser723Phe）先前被描述为未知意义的变体，但我们现在将其重新分类为可能的致病性。的极 变异体，c.1089C> A，p。（Asn363Lys）在一名从28岁开始患有三种异时性结直肠癌的患者中被发现，结果证明是 从头。一种致病性PMS2变体是新颖的。我们还发现了许多高度重要的，未知意义的变体。装甲运兵车， BUB1，TP53 和 RPS20。的RPS20 该变异体是新颖的，在一个具有多重肿瘤表型的大型阿姆斯特丹I阳性家庭中发现，包括早在24岁的12例CRC。该变异体被发现与该家族中的癌症分开，且多发性 在计算机上工具预测它是致病的。我们的数据进一步支持了从基于表型的癌症专家组向大型专家组的转变，包括涉及遗传性癌症综合征或（靶向）全基因组测序的所有已建立基因。此外，还确定了可能的疾病易感变种RPS20 扩展了表型 RPS20相关的癌症，并强调该基因与包括在大肠癌基因组中有关。