Submissions for variant NM_000314.8(PTEN):c.-765G>A

gnomAD frequency: 0.00002  dbSNP: rs587776674

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000230941	SCV000840498	uncertain significance	PTEN hamartoma tumor syndrome	2020-06-18	reviewed by expert panel	curation	PTEN c.-765G>A (AKA c.-764G>A, NC_000010.10:g.89623462G>A) 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	RCV000169801	SCV000222117	uncertain significance	not provided	2024-08-29	criteria provided, single submitter	clinical testing	Observed in individuals with breast or endometrial cancer (PMID: 17847000, 12844284); Published functional studies are inconclusive: 60% decrease in luciferase activity, but luciferase mRNA levels similar to wild type; lost protein-DNA interaction and decreased expression by enhanced yeast one-hybrid assay (PMID: 17847000, 25910213); No data available from control populations to assess the frequency of this variant; Describes a nucleotide substitution 765 basepairs upstream of the ATG translational start site in the PTEN promoter region; Also known as c.-764G>A; This variant is associated with the following publications: (PMID: 27569544, 18794875, 23825907, 12844284, 17847000, 23315997, 25910213, 27187382, 34426522)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230941	SCV000284573	uncertain significance	PTEN hamartoma tumor syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the PTEN gene. It does not change the encoded amino acid sequence of the PTEN protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with PTEN-related conditions (PMID: 12844284, 17847000). This variant is also known as c.-764G/A. ClinVar contains an entry for this variant (Variation ID: 7844). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 17847000, 25910213). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000008294	SCV000785100	uncertain significance	Cowden syndrome 1	2017-04-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763685	SCV000894565	uncertain significance	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; VACTERL with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390095	SCV002673838	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing	The c.-764G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 764 bases upstream from the first translated codon. This variant has been reported in two individuals (one with endometrial cancer, and one with breast cancer) from cohorts of individuals suspicious for Cowden syndrome (Teresi RE et al. Am. J. Hum. Genet. 2007 Oct;81(4):756-67; Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73(2):404-11). In one study, reporter assays indicated that this variant demonstrated an approximate 50% decrease in luciferase activity compared to wild type; however, this same study showed that this alteration had no effect on mRNA, suggesting no adverse effects on transcriptional efficiency due to this variant (Teresi et al.) This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114178	SCV003800723	uncertain significance	not specified	2023-01-09	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.-765G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 2e-05 in 150850 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-765G>A has been reported in the literature in individuals affected with Cowden Syndrome (Zhou_2003, Teresi_2007). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. Experimental evidence evaluating an impact on protein function provided conflicting results: the variant showed an inhibition in luciferase activity when compared to the wild-type, yet luciferase mRNA expression was similar to wild-type suggesting transcription efficiency was not compromised (Teresi_2007). A different study utilizing yeast one-hybrid assays, concluded loss of transcription factor binding and decreased expression (Furman Bass_2015). These studies do not allow convincing conclusions about the variant effect. Six ClinVar submitters including an expert panel (ClinGen PTEN Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003466837	SCV004206664	uncertain significance	Glioma susceptibility 2	2024-02-16	criteria provided, single submitter	clinical testing
OMIM	RCV000008294	SCV000028501	pathogenic	Cowden syndrome 1	2007-10-01	no assertion criteria provided	literature only