ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.882T>G (p.Ser294Arg) (rs143335584)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115588 SCV000187108 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
ClinGen PTEN Variant Curation Expert Panel RCV000205424 SCV000930145 uncertain significance PTEN hamartoma tumor syndrome 2019-03-05 reviewed by expert panel curation PTEN c.882T>G (p.S294R) 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.
Color RCV000115588 SCV000910875 likely benign Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing
Counsyl RCV000410224 SCV000488210 uncertain significance Cowden syndrome 1 2016-01-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515289 SCV000611428 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 RCV000589727 SCV000149497 uncertain significance not provided 2018-11-14 criteria provided, single submitter clinical testing This variant is denoted PTEN c.882T>G at the cDNA level, p.Ser294Arg (S294R) at the protein level, and results in the change of a Serine to an Arginine (AGT>AGG). This variant was observed in at least one individual with breast cancer and one individual with colorectal cancer (Tung 2015, Yurgelun 2017) and was also identified in 1/118 healthy Hispanic individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the latter study were younger than 50 years old, thus the unaffected status of that individual may not be significant. PTEN Ser294Arg was observed at an allele frequency of 0.06% (14/24,006) in individuals of African ancestry 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 Ser294Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121909 SCV000086113 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000589727 SCV000696544 uncertain significance not provided 2016-09-16 criteria provided, single submitter clinical testing Variant summary: The PTEN c.882T>G (p.Ser294Arg) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/122254 control chromosomes at a frequency of 0.0000736, which is approximately 12 times the estimated maximal expected allele frequency of a pathogenic PTEN variant (0.0000063), suggesting this variant is likely a benign polymorphism. However, due to the small number of carriers in this dataset, this data should be taken with caution. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as a VUS - possibly benign.
Invitae RCV000205424 SCV000260305 uncertain significance PTEN hamartoma tumor syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 294 of the PTEN protein (p.Ser294Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs143335584, ExAC 0.06%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127693). 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.
Mendelics RCV000205424 SCV000838423 uncertain significance PTEN hamartoma tumor syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121909 SCV000602131 uncertain significance not specified 2016-09-27 criteria provided, single submitter clinical testing

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