A new PMS2 gene variant of unknown significance: How pathogenic is it?

e13532 Background: The Lynch syndrome (LS) is the most common inherited syndrome associated with colorectal cancer (CRC). The hallmark of LS is DNA mismatch repair deficiency. The amount of variants of uncertain significance (VUS) in suspected LS confounds diagnosis, requiring surveillance of variant reclassifications. In this paper we describe a new and most likely pathogenic VUS in PMS2. Methods: Patient screened for personal and familial cancer and evaluated with NGS gene panels for 31 genes. The protein structure was analyzed with the software Pymol. Results: A woman diagnosed with breast cancer (BC) at 60 years and CRC at 65 years was investigated due to her extensive family history of cancer (21 maternal relatives), including 6/9 siblings [gastric n = 1, lung n = 1, BC n = 4 (one of whom with BC, endometrium and CRC)], 8/12 aunts and uncles, all of whom died of cancer (gastric n = 4, CRC n = 1, CNS n = 1, BC n = 1; uterus/gallbladder n = 1), and 7 cousins (CNS n = 3, lung n = 1, gastric n = 2, suspected ovary n = 1). The new PMS2 gene variant c.134A > G(p.Asn45Ser), which was also detected in two sisters with CRC submitted to segregation analysis, occupied the same locus as a known pathogenic variant, c.134A > C(p.Asn45Thr). The structural analysis showed that the mutated locus encodes a serine instead of an asparagine in position 45 at the enzyme’s active site. Asn 45 is a conserved amino acid that binds to ATP in protein structure (PDB = 1EA6). Interestingly, this is close to position 42-44, for which another potentially pathogenic VUS (p.Leu42_Glu44del) has been described. Conclusions: Based on our patient’s personal and family history and on the locus variant and protein structure analysis, the new PMS2 gene variant described in this paper is most likely pathogenic.