Characterization of a germline splice site variant MLH1 c.678-3T>A in a Lynch syndrome family
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ORIGINAL ARTICLE
Characterization of a germline splice site variant MLH1 c.678‑3T>A in a Lynch syndrome family Ciyu Yang1 · Margaret Sheehan2 · Ester Borras1 · Karen Cadoo2 · Kenneth Offit2 · Liying Zhang3
© Springer Nature B.V. 2020
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. Keywords MLH1 · Germline · c.678-3T>A · Lynch syndrome · Splice site variant
Introduction Lynch syndrome (LS), also called Hereditary Non-Polyposis Colorectal Cancer (HNPCC) [1], is an autosomal dominant inherited disease accounting for approximately 1–5% of all diagnosed colorectal cancers (CRC) [2]. It is characterized by an increased risk of early onset cancers including colorectum, endometrium, ovarian, small bowel, stomach, hepatobiliary, urinary, small bowel, brain or central nervous system, as well as sebaceous tumors [3]. Lynch syndrome is caused by a defect in the DNA mismatch repair (MMR) pathway due to the presence of germline pathogenic variants in the MMR genes [4] with mutations in MLH1 and * Liying Zhang [email protected] 1
Departments of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
2
Departments of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
3
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles (UCLA), 10833 Le Conte Ave, Los Angeles, CA 90095, USA
MSH2 identified in almost 90% of LS patients [5]. Germline mutations in MMR genes lead to tumors with characteristic mutational signature, microsatellite instability (MSI), and loss of expression of one or more MMR proteins [6]. Many MMR gene mutations identified to date are truncating variants (nonsense and small insertions/deletions), large deletions/duplications and splice site variants affecting the highly conserved intronic dinucleotides 5′ GT and 3′ AG [7]. These variants are considered clinically significant as they clearly disrupt the normal function of the pr
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