Submissions for variant NM_000447.3(PSEN2):c.640G>T (p.Val214Leu)

gnomAD frequency: 0.00011  dbSNP: rs574125890

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002070239	SCV002404527	benign	Alzheimer disease 4	2023-11-27	criteria provided, single submitter	clinical testing
Mendelics	RCV002246336	SCV002519764	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002246336	SCV005185393	likely benign	not specified	2024-05-07	criteria provided, single submitter	clinical testing	Variant summary: PSEN2 c.640G>T (p.Val214Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251450 control chromosomes, predominantly at a frequency of 0.0032 within the East Asian subpopulation in the gnomAD database. c.640G>T has been reported in the literature in individuals affected with Alzheimer Disease, without strong evidence for causality (example, Koriath_2020, Liang_2023, Youn_2014 ). These report(s) 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: 30279455, 37051054, 24885952). ClinVar contains an entry for this variant (Variation ID: 1050746). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358553	SCV001554321	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PSEN2 p.Val214Le variant was identified in 2 of 192 proband chromosomes (frequency: 0.0104) from two individuals of Chinese Han ancestry with early-onset Alzheimer’s disease (EOAD) and was not identified in 292 control chromosomes from healthy individuals (Shi_2015_PMID:25323700). One patient with EOAD had a family history of dementia and the other patient did not; it was concluded that the p.V214L variant may modify the risk for dementia (Shi_2015_PMID:25323700). The variant was not identified in ClinVar, Cosmic or LOVD 3.0 but was identified in dbSNP (ID: rs574125890) and in control databases in 73 of 282836 chromosomes at a frequency of 0.000258 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 71 of 19950 chromosomes (freq: 0.003559) and European (non-Finnish) in 2 of 129154 chromosomes (freq: 0.000015), it was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), Other, and South Asian populations. The p.Val214 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.