Submissions for variant NM_000314.8(PTEN):c.882T>G (p.Ser294Arg) (rs143335584)

Total submissions: 11

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