Background: MSH2 germ line pathogenic variants are a well-recognized cause of Lynch syndrome, predisposing individuals to a variety of malignancies, most usually colorectal and endometrial cancer. Partial duplications of MSH2 gene, due to their position in the genome and frequently unclear mechanisms of pathogenicity, are often classified as Variants of Uncertain Significance (VUS).
Case presentation: CNV (Copy Number Variation) analysis revealed a duplication of MSH2 exon 15 in a young male patient with colorectal cancer as well as in his affected family members. RNA analysis elucidated the impact of this duplication on RNA, revealing that it leads to an abnormal transcript, thus providing experimental evidence for a pathogenic effect.
Conclusions: We show that the combination of CNV and RNA analysis provides critical information for the identification and proper classification of pathogenic/ likely pathogenic variants which, in turn, is of
great importance for the patients as well as for their family members
with an actionable impact in clinical practice.