Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome. Classification and interpretation of intronic variants, especially those outside the consensus ± 1 ~ 2 splice sites are challenging as it is uncertain whether such variants would affect splicing accuracy and efficiency. The assessment of the pathogenicity of splice site variants in MLH1 is further complicated by the various isoforms due to alternative splicing. In this report, we describe a 42-year-old female with Lynch syndrome who carries a germline variant, MLH1 c.678-3T>A, in the splice acceptor site of intron 8. Functional studies and semiquantitative analysis demonstrated that this variant causes a significant increase in the transcripts with exon 9 or exon 9 and 10 deletions, which presumably leads to premature protein truncation or abnormal protein. In addition, we also observed MSI-H and loss of MLH1 by IHC in patient’s tumor tissue. This variant also segregated with Lynch Syndrome related cancers in three affected family members. Based on these evidence, the MLH1 c.678-3T>A variant is considered pathogenic.

中文翻译：

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Lynch综合征家族中生殖系剪接位点变体MLH1 c.678-3T> A的特征。

DNA错配修复（MMR）基因中的种系突变导致Lynch综合征。内含子变体的分类和解释，特别是那些在一致的±1〜2个剪接位点之外的变体，具有挑战性，因为尚不确定此类变体是否会影响剪接的准确性和效率。由于替代剪接，各种同工型使MLH1中剪接位点变异的致病性评估更加复杂。在本报告中，我们描述了具有Lynch综合征MLH1的42岁女性Lynch综合征c.678-3T> A，位于内含子8的剪接受体位点。功能研究和半定量分析表明，此变异体导致外显子9或外显子9和10缺失的转录本显着增加，这可能导致蛋白质过早截短。或异常蛋白质。此外，我们还观察了IHC在患者肿瘤组织中的MSI-H和MLH1的丢失。在三个受影响的家庭成员中，该变体还与Lynch综合征相关的癌症分开。根据这些证据，认为MLH1 c.678-3T> A变体具有致病性。