Abstract
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.
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This study was funded by Department of Pathology, Memorial Sloan Kettering Cancer Center.
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Dr. Cadoo reports institutional support for therapeutic clinical trial, travel and expenses from Astra Zeneca, institutional support for therapeutic clinical trial from Syndax Pharmaceuticals, personal fees and other from Tessaro, personal fees from OncLive, outside the submitted work. Dr. Zhang: honoraria (future technology research LLC, BGI, Illumina); honoraria and travel and accommodation expenses (Roche Diagnostics Asia Pacific). Family member has a leadership position and ownership interest of Shanghai Genome Center. The other authors do not have any conflict of interest.
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Yang, C., Sheehan, M., Borras, E. et al. Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family. Familial Cancer 19, 315–322 (2020). https://doi.org/10.1007/s10689-020-00180-7
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DOI: https://doi.org/10.1007/s10689-020-00180-7