Introduction

Lynch syndrome (LS) is predisposing mainly to colorectal and endometrial carcinomas, but also to urinary tract cancers. LS association with upper urinary tract carcinomas is known, but its association with bladder cancer is not so clear. Confirmation of pathogenicity of detected mutations in LS-associated genes is required for adequate counseling.

Material and Methods

Tested young female has family history of two early colorectal and two bladder carcinomas. NGS sequencing revealed MSH2 splice site mutation c.2634+1G>C, which was confirmed by Sanger sequencing. MSH2 cDNA part containing potential splicing change was sequenced. in silico softwares were used to predict the effect of detected mutation on splicing and protein structure. ACMG Guidelines were used for mutation classification.

Results

in silico softwares predict damaging effect of detected mutation on splicing and loss of protein-binding domains. cDNA sequencing confirmed this mutation causes exon 15 excision. ACMG Guidelines classify this mutation as Pathogenic.

Discussion

MSH2 c.2634+1G>C mutation was not reported previously as LS associated. We confirmed its damaging effect on splicing. in silico tools predict consequent loss of protein domains implicating disrupted protein function. Our results suggest that this mutation should be classified as Pathogenic, and indicate inclusion of bladder cancer in LS cancer spectrum.

中文翻译：

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确认MSH2 c.2634 + 1G> C突变对剪接的破坏作用，其分类和对咨询的意义。

介绍

Lynch综合征（LS）主要易患结直肠癌和子宫内膜癌，也易患尿路癌。LS与上尿路癌的关联是已知的，但与膀胱癌的关联尚不清楚。LS咨询相关基因突变的致病性的确认需要充分的咨询。

材料与方法

经过测试的年轻女性有两个早期大肠癌和两个膀胱癌的家族史。NGS测序显示MSH2剪接位点突变c.2634 + 1G> C，已通过Sanger测序证实。测序含有潜在剪接变化的MSH2 cDNA部分。in silico软件中的软件用于预测检测到的突变对剪接和蛋白质结构的影响。ACMG指南用于突变分类。

结果

silico软件中的软件可预测检测到的突变对剪接和蛋白质结合域丢失的破坏作用。cDNA测序证实该突变引起外显子15切除。ACMG指南将此突变分类为病原性。

讨论区

MSH2 c.2634 + 1G> C突变以前没有报道为与LS相关。我们证实了其对拼接的破坏作用。在计算机工具中，预测到蛋白质结构域的丢失会导致蛋白质功能的破坏。我们的结果表明，该突变应归为致病突变，并表明在LS癌症谱中包括了膀胱癌。