Submissions for variant NM_000314.8(PTEN):c.882T>G (p.Ser294Arg)

gnomAD frequency: 0.00029  dbSNP: rs143335584

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000205424	SCV000930145	likely benign	PTEN hamartoma tumor syndrome	2023-08-04	reviewed by expert panel	curation	NM_000314.8(PTEN):c.882T>G (p.Ser294Arg) 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: Filtering allele frequency of 0.0002887 (0.02887%, 13/24922 African/African American alleles) in gnomAD. BP4: REVEL score = 0.365. 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 (-4 pts), BP4 (-1 pt), PP2 (+1 pt) = -4 pts total (Likely Benign).
GeneDx	RCV000589727	SCV000149497	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with breast or colorectal cancer (Tung 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 23161105, 29785012, 24728327, 26800850, 28135145, 27720647, 29272070, 25186627, 33796447, 33887726, 18626510)
Ambry Genetics	RCV000115588	SCV000187108	likely benign	Hereditary cancer-predisposing syndrome	2019-06-11	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	RCV000205424	SCV000260305	benign	PTEN hamartoma tumor syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000410224	SCV000488210	uncertain significance	Cowden syndrome 1	2016-01-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589727	SCV000602131	likely benign	not provided	2022-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477278	SCV000611428	uncertain significance	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; Glioma susceptibility 2; Cowden syndrome 1	2022-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121909	SCV000696544	likely benign	not specified	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.882T>G (p.Ser294Arg) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 1614844 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database (gnomAD v4.1.0). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTEN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (1.6e-05). c.882T>G has been reported in the literature in individuals affected with various types of cancers including but not limited to neuroblastoma, colorectal cancer and prostate cancer (example: Zhang_2015, Yurgelun_2017, Coelho_2024). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 25186627, 28135145, 26580448, 26800850, 23161105, 38311546). ClinVar contains an entry for this variant (Variation ID: 127693). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000205424	SCV000838423	uncertain significance	PTEN hamartoma tumor syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115588	SCV000910875	likely benign	Hereditary cancer-predisposing syndrome	2022-11-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000121909	SCV002069034	uncertain significance	not specified	2021-06-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PTEN gene demonstrated a sequence change, c.882T>G, in exon 8 that results in an amino acid change, p.Ser294Arg. This sequence change has been described in the gnomAD database with a frequency of 0.052% in the African American/African subpopulation (dbSNP rs143335584). The p.Ser294Arg change affects a moderately conserved amino acid residue located in a domain of the PTEN protein that is known to be functional. The p.Ser294Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in one individual with colorectal cancer who underwent germline genetic testing and it was considered a variant of unknown significance (PMID: 28135145). Due insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser294Arg change remains unknown at this time.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251985	SCV002523647	uncertain significance	See cases	2020-04-07	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP2, BP4
Sema4, Sema4	RCV000115588	SCV002528273	likely benign	Hereditary cancer-predisposing syndrome	2020-10-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410224	SCV004019896	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000589727	SCV004225287	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	PP2
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000115588	SCV005402546	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 GRCh38:10:87960974:T>G was assigned evidence codes ['BS3_Supporting', 'BP4', 'BA1'] and an overall classification of Benign
ITMI	RCV000121909	SCV000086113	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004542818	SCV004790540	likely benign	PTEN-related disorder	2024-01-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect - Brain Gene Registry	RCV003987363	SCV004804572	not provided	Macrocephaly-autism syndrome; Cowden syndrome 1		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 11-19-2020 by USAF Medical Genetics Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.