Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226888116 C>G
Position: (GRCh37/hg19):Chr1:227075817 C>G
dbSNP ID: rs775145486
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCT to TGT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in an Italian kindred. The proband developed insidious memory loss at age 60, followed by progressive dementia and the diagnosis of probable Alzheimer's disease. There was a family history of dementia; the proband's mother had experienced dementia at age 60, and two of the mother's siblings had memory disturbances before the age of 65. The proband had two affected siblings who also carried the mutation. For the three siblings, the mean age of onset was 63 years.  In addition to progressive memory decline, the clinical course in the siblings was characterized by mood changes (primarily depression and apathy), and the proband experienced extrapyramidal signs, namely rigidity and bradykinesia. The mode of inheritance was consistent with autosomal-dominant transmission with high penetrance. The mutation was absent in 247 unrelated individuals (117 healthy controls and 130 individuals with AD) (Piscopo et al., 2010).

The mutation is found in the gnomAD variant database with a single allele count and a frequency of 0.000004805 (gnomAD v2.1.1 (non-neuro), Apr 2021).

Neuropathology

Unknown. MRI of the proband's brain showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions (Piscopo et al., 2010).

Biological Effect

In a cell-based assay, this variant increased Aβ42 levels and the Aβ42/Aβ40 ratio, without significantly altering Aβ40 levels compared to cells expressing wildtype PSEN2 (Marsh et al, 2025).

This variant results in the substitution of an evolutionarily conserved residue in the third transmembrane domain of PSEN2. In silico algorithms have predicted it is probably damaging (Polyphen) and deleterious (SIFT) (gnomAD v2.1.1 (non-neuro), Apr 2021) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Nov 2021).

This variant has been classified as "definitely pathogenic" (Piscopo et al., 2010) and, more recently, as "likely pathogenic" (Liu et al., 2025).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*Carriers of this variant are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025).

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Piscopo P, Talarico G, Crestini A, Gasparini M, Malvezzi-Campeggi L, Piacentini E, Lenzi GL, Bruno G, Confaloni A. A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. J Alzheimers Dis. 2010;20(1):43-7. PubMed.
2. Marsh JA, Huang G, Bowling K, Renton AE, Ziegemeier E, Ball T, Pottier C, Cruchaga C, Day GS, Bateman RJ, Llibre-Guerra JJ, McDade E, Karch CM. Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2. Neurotherapeutics. 2025 Jan 27;:e00527. Epub 2025 Jan 27 PubMed.
3. Liu H, Marsh TW, Shi X, Renton AE, Bowling KM, Ziegemeier E, Wang G, Cao Y, Aristel A, Li J, Dickson A, Perrin RJ, Goate AM, Fernández V, Day GS, Doering M, Daniels A, Gordon BA, Benzinger TL, Hassenstab J, Ibanez L, Supnet-Bell C, Xiong C, Allegri R, Berman SB, Fox NC, Ryan N, Huey ED, Vöglein J, Noble JM, Roh JH, Jucker M, Laske C, Ikeuchi T, Sanchez-Valle R, Schofield PR, Chrem Mendez P, Chhatwal JP, Farlow M, Lee JH, Levey AI, Levin J, Lopera F, Martins R, Niimi Y, Rosa-Neto P, Morris JC, Bateman RJ, Karch CM, Cruchaga C, McDade E, Llibre-Guerra JJ. The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset. Brain. 2025 Feb 4; Epub 2025 Feb 4 PubMed.

External Citations

1. gnomAD v2.1.1 (non-neuro), Apr 2021
2. gnomAD v2.1.1 (non-neuro), Apr 2021

Further Reading