ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) (rs371387815)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000199677 SCV000930147 uncertain significance PTEN hamartoma tumor syndrome 2019-03-05 reviewed by expert panel curation PTEN c.892C>G (p.Q298E) 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). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350)
GeneDx RCV000656956 SCV000149499 uncertain significance not provided 2019-09-10 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with a Lynch syndrome-associated cancer and/or polyps who also harbored a pathogenic MLH1 variant (Yurgelun 2015); Published functional studies demonstrate no damaging effect: phosphatase activity comparable to wild-type in a high-throughput assay (Mighell 2018); This variant is associated with the following publications: (PMID: 25695693, 25980754, 24055113, 26800850, 27150160, 31006514, 29706350)
Ambry Genetics RCV000115590 SCV000186482 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing The p.Q298E variant (also known as c.892C>G), located in coding exon 8 of the PTEN gene, results from a C to G substitution at nucleotide position 892. The glutamine at codon 298 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000199677 SCV000254528 uncertain significance PTEN hamartoma tumor syndrome 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 298 of the PTEN protein (p.Gln298Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual with suspected Lynch syndrome who also carried a pathogenic variant in MLH1 (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127695). Experimental studies have shown that this variant does not substantially affect PTEN protein function (PMID: 32350270). 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 RCV000148765 SCV000489541 uncertain significance Cowden syndrome 1 2016-10-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515394 SCV000611429 uncertain significance Endometrial carcinoma; Macrocephaly/autism syndrome; Meningioma, familial; Squamous cell carcinoma of the head and neck; Bannayan-Riley-Ruvalcaba syndrome; Malignant tumor of prostate; Thyroid cancer, nonmedullary, 2; VACTERL association with hydrocephalus; Glioma susceptibility 2; Cowden syndrome 1; Cutaneous malignant melanoma 1 2017-05-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212885 SCV000731490 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing The p.Gln298Glu variant in PTEN has been reported in 1 individual with a Lynch s yndrome-associated cancer and/or colon polyps (Yurgelun 2015). This variant has also been reported in ClinVar (associated phenotypes include PTEN hamartoma synd rome and hereditary cancer predisposition syndrome syndrome, Variation ID# 12769 5). This variant has been identified in 2/10354 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs371387815 ).Computational prediction tools suggest that the p.Gln298Glu variant may not im pact the protein, though this information is not predictive enough to rule out p athogenicity. In summary, the clinical significance of the p.Gln298Glu variant i s uncertain.
Color Health, Inc RCV000115590 SCV000903084 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-26 criteria provided, single submitter clinical testing This missense variant replaces glutamine with glutamic acid at codon 298 of the PTEN protein. Functional studies have shown that the variant proteins displays phenotypes similar to the wild-type protein in yeast, drosophila, and mammalian cell-based assays (PMID: 32350270). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 5/282198 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Division of Medical Genetics, University of Washington RCV000148765 SCV001434310 uncertain significance Cowden syndrome 1 2020-01-22 criteria provided, single submitter clinical testing This variant has been reported in the literature in an individual with a Lynch syndrome-associated cancer and/or polyps who also had a pathogenic variant in the MLH1 gene (Yurgelun 2015). This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
CSER _CC_NCGL, University of Washington RCV000148765 SCV000190502 uncertain significance Cowden syndrome 1 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354793 SCV001549494 uncertain significance Familial ovarian cancer no assertion criteria provided clinical testing The PTEN p.Gln298Glu variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with HNPCC and was present in 1 of 2000 control chromosomes (frequency: 0.0005) from individuals participating in an exome sequencing study of incidental findings (Yurgelun 2015, Dorschner 2013). The variant co-occurred with an MLH1 variant (duplication of exons 6-12) in 1 affected patient (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs371387815) “With Pathogenic, Uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Counsyl, Fulgent Genetics, LMM, GeneDx, Ambry Genetics and CSER_NCGL University of Washington Medical Center). It was not identified in Cosmic, MutDB, LOVD 3.0 or the Zhejiang University Database. The variant was identified in control databases in 5 of 276588 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 23980 chromosomes (freq: 0.0002) and European Non-Finnish in 1 of 126380 chromosomes (freq: 0.000008), while it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Gln298 residue is conserved in mammals but not in more distantly related organisms. However, 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.