A Lynch syndrome patient with multiple cancers who was found to have a novel pathogenic variant generating aberrant splicing of MLH1.
Ayumi Abe, Hidetaka Eguchi, Kimio Matsumura et al.
✦ AI-curated · Sources linked
Case in brief
A Japanese woman with colorectal, gastric, and endometrial cancers was found to carry the germline MLH1 variant c.545G>T (p.Arg182Met), initially classified by a clinical testing laboratory as a variant of uncertain significance. Because the change lies at the final nucleotide of exon 6, in silico analyses predicted altered splicing. RT-PCR of peripheral-blood-cell RNA confirmed skipping of the entire exon, producing a premature stop codon (p.Glu153Phefs*8). Applying ACMG/AMP guidelines, the authors reclassified the variant as likely pathogenic; further analysis enabled carrier diagnosis in relatives.
What made this case unusual
A missense variant at the last nucleotide of MLH1 exon 6 was associated with complete exon skipping, illustrating how a change annotated as missense can disrupt splicing.
Diagnostic / clinical pearl
When an MLH1 variant near an exon boundary remains uncertain, RNA analysis can help establish whether it causes aberrant splicing and inform variant classification.