A Novel Germline <i>MLH1</i> In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue

• Main Authors: Gašper Klančar, Ana Blatnik, Vita Šetrajčič Dragoš, Vesna Vogrič, Vida Stegel, Olga Blatnik, Primož Drev, Barbara Gazič, Mateja Krajc, Srdjan Novaković
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Genes
• Subjects: lynch syndrome; mmr; novel <i>mlh1</i> variant; segregation analysis; isolated pms2 loss
• Online Access: https://www.mdpi.com/2073-4425/11/3/325

The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel <i>MLH1</i> in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in <i>MLH1</i>. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel <i>MLH1</i> variant as likely pathogenic, we confirmed the LS in this family.