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

gnomAD frequency: 0.00009  dbSNP: rs371387815

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000199677	SCV000930147	likely benign	PTEN hamartoma tumor syndrome	2023-08-04	reviewed by expert panel	curation	NM_000314.8(PTEN):c.892C>G (p.Gln298Glu) meets criteria to be classified as likely benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1_Supporting: Filtering allele frequency of 0.00002132 (0.002132%, 4/24900 African/African American alleles) in gnomAD. BS3_Supporting: Massively parallel functional assay interrogating phosphatase activity demonstrating no statistically significant difference from wild type (PMID: 29706350). BP4: REVEL score = 0.229. 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. Variant with benign and pathogenic codes. Classification based on application of Bayesian Classification Framework (PMID: 29300386): BS1_P (-1 pt1), BS3_P (-1 pt), BP4 (-1 pt), PP2 (+1 pt) = -2 pts total (Likely Benign).
GeneDx	RCV000656956	SCV000149499	uncertain significance	not provided	2022-09-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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 et al., 2015); Published functional studies demonstrate no damaging effect: protein stability and phosphatase activity generally comparable to wild-type (Mighell et al., 2018; Post et al., 2020); This variant is associated with the following publications: (PMID: 25695693, 24055113, 26800850, 27150160, 31006514, 18626510, 32350270, 25980754, 29706350)
Ambry Genetics	RCV000115590	SCV000186482	likely benign	Hereditary cancer-predisposing syndrome	2024-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199677	SCV000254528	uncertain significance	PTEN hamartoma tumor syndrome	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 298 of the PTEN protein (p.Gln298Glu). This variant is present in population databases (rs371387815, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127695). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect PTEN 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; Familial meningioma; Squamous cell carcinoma of the head and neck; Bannayan-Riley-Ruvalcaba syndrome; Malignant tumor of prostate; Thyroid cancer, nonmedullary, 2; VACTERL with hydrocephalus; Glioma susceptibility 2; Cowden syndrome 1; Melanoma, cutaneous malignant, susceptibility to, 1	2017-05-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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 Diagnostics, LLC DBA Color Health	RCV000115590	SCV000903084	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	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: 29706350, 32350270). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), but also in a control cohort (PMID: 24055113). 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
Genetic Services Laboratory, University of Chicago	RCV000212885	SCV002069006	uncertain significance	not specified	2018-04-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212885	SCV002600619	uncertain significance	not specified	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.892C>G (p.Gln298Glu) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain (IPR014020) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251224 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.892C>G has been reported in the literature in an individual affected with Lynch Syndrome (example: Yurgelun_2015). However, this individual also had a co-occurrence with other pathogenic variant (MLH1 c.454-?_1409+?dup/dup exons 6-12), providing supporting evidence for a benign role. Experimental studies have shown that this variant does not alter protein function (examples: Mighell_2018 and Post_2020). Ten submitters (including an expert panel) have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000148765	SCV004019906	uncertain significance	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Genetics and Molecular Pathology, SA Pathology	RCV003447497	SCV004175539	uncertain significance	Familial cancer of breast	2020-08-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467048	SCV004206668	uncertain significance	Glioma susceptibility 2	2023-09-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000199677	SCV004838586	uncertain significance	PTEN hamartoma tumor syndrome	2024-07-20	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: 29706350, 32350270). This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754), in an individual affected with ovarian cancer (PMID: 32885271), but also in a control cohort (PMID: 24055113). 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.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000115590	SCV005402548	likely benign	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	curation	Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).For PTEN, two assays measuring activity and abundance were used. If the abundance was categorized as "wt-like" or "possibly wt-like," BS3_Supporting evidence was used. Furthermore, if the cumulative score was greater than -5, BS3_moderate evidence was used. This variant GRCh38:10:87960984:C>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BS1'] and an overall classification of Likely benign
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.
PreventionGenetics, part of Exact Sciences	RCV004734654	SCV005355605	uncertain significance	PTEN-related disorder	2024-05-20	no assertion criteria provided	clinical testing	The PTEN c.892C>G variant is predicted to result in the amino acid substitution p.Gln298Glu. This variant has been previously reported in at least one individual with suspected Lynch syndrome, who also had a large duplication in the MLH1 gene (Yurgelun et al. 2015. PubMed ID: 25980754). A mutation saturation study assessing in silico and functional data suggests this variant does not significantly impact protein function (Mighell et al. 2018. PubMed ID: 29706350, Table S2). It is reported in 5 of ~282,000 alleles in gnomAD. It is interpreted as likely benign by the ClinGen PTEN Variant Curation Expert Panel in ClinVar and as uncertain significance by other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/127695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.