10-87863704-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000314.8(PTEN):c.-766G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000314.8 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.-766G>A | 5_prime_UTR_variant | Exon 1 of 9 | ENST00000371953.8 | NP_000305.3 | ||
PTEN | NM_001304717.5 | c.-246G>A | 5_prime_UTR_variant | Exon 1 of 10 | NP_001291646.4 | |||
PTEN | NM_001304718.2 | c.-1471G>A | 5_prime_UTR_variant | Exon 1 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 241082Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 122542
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
PTEN-related disorder Uncertain:1
The PTEN c.-765G>A variant is located in the 5' untranslated region. This variant (also referred to as -764A-G, c.-764G>A, and -764G/A using alternative nomenclature) occurs in the pre-coding region of the gene. This variant has been identified in individuals affected with Cowden syndrome who also had breast or endometrial cancer (Zhou et al. 2003. PubMed ID: 12844284; Teresi et al. 2007. PubMed ID: 17847000). In a reporter assay, this variant demonstrated ~50% decrease in luciferase activity compared to wild type; however, luciferase mRNA expression was equal to that of wild type in cells transfected with the wild type construct (Teresi et al. 2007. PubMed ID: 17847000). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/7844/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.-765G>A variant is located in the 5' untranslated region (5’UTR) of the PTEN gene. This variant results from a G to A substitution 765 nucleotides upstream from the first translated codon. In one study, this variant was described in an individual with breast cancer (Zhou XP et al. Am J Hum Genet. 2003;73(2):404-411). In another study, this variant was described in a patient with benign breast neoplasia and endometrial cancer (Teresi RE et al. Am. J. Hum. Genet. 2007 Oct;81(4):756-67). This same study demonstrates that PTEN transcription efficiency and mRNA stability were not compromised, although the c.-765G>A alteration did result in a decrease of luciferase activity as measured by an in vitro reporter assay. In addition, in silico analysis predicted that the mRNA secondary structure of the PTEN promoter was altered. Based on the above evidence, the authors hypothesized that the c.-765G>A variant would result in a significant decrease in protein expression. Of note, this variant is also known as -764G>A in published literature. In addition, this nucleotide position is highly conserved in available vertebrate species. Since supporting evidence for this variant is limited at this time, the clinical significance of this alteration is unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at