ClinVar Miner

Submissions for variant NM_000314.8(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
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.
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.
Ambry Genetics RCV000115588 SCV000187108 likely benign Hereditary cancer-predisposing syndrome 2019-06-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000205424 SCV000260305 benign PTEN hamartoma tumor syndrome 2019-12-23 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 uncertain significance not provided 2020-08-03 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; 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
Integrated Genetics/Laboratory Corporation of America RCV000121909 SCV000696544 likely benign not specified 2020-10-15 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 7e-05 in 283688 control chromosomes, predominantly at a frequency of 0.00052 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 33 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.882T>G has been reported in the literature in individuals affected with neuroblastoma or colorectal cancer (Zhang_2015, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x), likely benign (2x) and benign (1x). 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 RCV000115588 SCV000910875 likely benign Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing
ITMI RCV000121909 SCV000086113 not provided not specified 2013-09-19 no assertion provided reference population

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