Submissions for variant NM_000314.8(PTEN):c.-799G>C

gnomAD frequency: 0.00003  dbSNP: rs587779992

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000232535	SCV000863481	uncertain significance	PTEN hamartoma tumor syndrome	2020-06-18	reviewed by expert panel	curation	PTEN c.-798G>C (NC_000010.10:g.89623428G>C) 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). No criteria currently apply to this variant.
GeneDx	RCV000258981	SCV000149478	uncertain significance	not provided	2024-03-04	criteria provided, single submitter	clinical testing	Reported in at least one patient with Cowden syndrome and was absent in 186 controls (PMID: 17847000, 25669429); Functional studies did not identify any transcriptional or translational modifications affecting PTEN protein expression (PMID: 17847000); No data available from control populations to assess the frequency of this variant; Also known as c.-798G>C; This variant is associated with the following publications: (PMID: 23825907, 23315997, 25669429, 17847000)
Ambry Genetics	RCV000115569	SCV000185531	likely benign	Hereditary cancer-predisposing syndrome	2013-12-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232535	SCV000284574	likely benign	PTEN hamartoma tumor syndrome	2024-04-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000232535	SCV001138120	benign	PTEN hamartoma tumor syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804844	SCV002050809	uncertain significance	not specified	2021-12-07	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.-799G>C affects a conserved nucleotide that is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 2.6e-05 in 152060 control chromosomes in the gnomAD database (v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.-799G>C (aka c.-798G>C), has been reported in the literature in an individual affected with Cowden Syndrome (Teresi_2007, Nizialek_2015). However, these data do not allow clear conclusions about variant significance. One publication also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't affect in vitro protein binding to the PTEN promoter DNA segment, did not alter mRNA expression in transfected cells, and no difference in PTEN protein level was observed compared to the WT in patient derived lymphoblastoid cell lines (Teresi_2007). Four submitters, including an expert panel (ClinGen PTEN Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=2; including the expert panel), likely benign (n=1), and benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.