ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.892C>G (p.Gln298Glu) (rs371387815)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115590 SCV000186482 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148765 SCV000190502 uncertain significance Cowden syndrome 1 2014-06-01 no assertion criteria provided research
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)
Color RCV000115590 SCV000903084 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
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; Follicular thyroid carcinoma; VACTERL association with hydrocephalus; Glioma susceptibility 2; Cowden syndrome 1; Cutaneous malignant melanoma 1 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000656956 SCV000149499 uncertain significance not provided 2018-07-20 criteria provided, single submitter clinical testing This variant is denoted PTEN c.892C>G at the cDNA level, p.Gln298Glu (Q298E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has been identified in an individual with a Lynch syndrome-associated cancer and/or polyps who also harbored a pathogenic MLH1 variant (Yurgelun 2015). PTEN Gln298Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the C2 domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PTEN Gln298Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000199677 SCV000254528 uncertain significance PTEN hamartoma tumor syndrome 2018-12-24 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 reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127695). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
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.

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