ClinVar

Description

Variant summary: PSEN2 c.53C>T (p.Thr18Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.53C>T has been reported in the literature as a VUS in settings of WES in an individual affected with Parkinson's Disease (Blauwendraat_2016) and in a 17-year-old individual with vascular dementia, epilepsy and psychiatric features (Monkare_2021). These reports do not provide unequivocal conclusions about association of the variant with Alzheimer Disease 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26522186, 33268848). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.