ClinVar Genomic variation as it relates to human health

PTEN c.-835C>T, also described as c.-834C>T (NC_000010.10:g.89623392C>T) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). BS1_P: Allele frequency of 0.0002207 (0.02207%, 15/67980 alleles) in the European subpopulation of the gnomAD cohort, v3.1.2. (PMID 27535533)

Variant summary: PTEN c.-835C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.00011 in 144592 control chromosomes. The observed variant frequency is approximately 17.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Cowden Syndrome phenotype (6.3e-06), suggesting that the variant is benign. c.-835C>T has been reported in the literature in individuals affected with Cowden Syndrome (e.g. Zhou_2003, Teresi_2007, Ngeow_2011, Tan_2011, Liu_2013 Ngeow_2014, Nizialek_2015). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. One study (Black_2017) indicates the variant to have been observed in 10 controls, however, the nature of this cohort is not entirely clear other than stating the individuals did not have a personal history of cancer (ie, age or family history not provided). In addition, one functional study (Teresi_2007) found the variant to not have an impact on PTEN protein expression, while another functional study utilizing a yeast two-hybrid system suggested the variant causes the interaction with the associated transcription factor to be lost (Fuxman-Bass_2015). Nine ClinVar submitters (evaluation after 2014), including the ClinGen PTEN Variant Curation Expert Panel, have cited the variant, with all labs classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly benign.

Observed in individuals meeting either 'relaxed' or classic diagnostic criteria for Cowden syndrome per the International Cowden Consortium criteria and did not show a significant association with breast cancer in a case-control study (PMID: 12844284, 17847000, 21956414, 35172517); Published functional studies did not identify any transcriptional or translational modifications affecting PTEN protein expression (PMID: 17847000); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.-834C>T; This variant is associated with the following publications: (PMID: 27187382, 21956414, 25910213, 25669429, 24778394, 21194675, 23825907, 35172517, 26229595, 12844284, 12938083, 17847000)

The PTEN c.-315C>T variant is located in the 5' untranslated region. This variant (also referred to as c.-834C>T) has been reported in at least three patients with Cowden syndrome or a Cowden syndrome-like phenotype (Teresi et al. 2007. PubMed ID: 17847000; Ngeow et al. 2011. PubMed ID: 21956414). Similar sequence variants in the PTEN promoter have been shown to disrupt gene expression and have been associated with PTEN-related disorders (Zhou et al. 2003. PubMed ID: 12844284). This variant was shown to disrupt transcription factor binding by one assay (Fuxman Bass. 2015. PubMed ID: 25910213); however, transcription factor binding and PTEN activity was unaffected in a separate analysis (Teresi et al. 2007. PubMed ID: 17847000). This variant is reported in just one of ̴ 31,000 alleles in the gnomAD database, and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127676/). At this time, we interpret this change as a variant of uncertain significance due to the absence of conclusive functional and genetic evidence.