Submissions for variant NM_000314.7(PTEN):c.210-1G>A (rs1114167621)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491234	SCV000579959	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-09	criteria provided, single submitter	clinical testing	The c.210-1G>A intronic pathogenic mutation, results from a G to A one nucleotide upstream from coding exon 4 of the PTEN gene. This mutation has been reported in multiple individuals with classic Cowden syndrome and Cowden Syndrome-like features (Celebi JT et al. Hum. Genet. 2000 Sep; 107(3):234-8; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec; 96(12):E2063-71; Chen HJ et al. Hum. Mutat. 2017 10;38(10):1372-1377; Heald B et al. Gastroenterology 2010 Dec;139(6):1927-33; Mester J et al. Urology 2012 May;79(5):1187.e1-7; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43). In addition, mRNA studies performed have shown that this mutation results in out-of-frame skipping of exon 4 and a premature termination codon in exon 5 (Celebi JT et al. Hum. Genet. 2000 Sep;107(3):234-8; Chen HJ et al. Hum. Mutat. 2017 10;38(10):1372-1377). <span style="background-color:initial">In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507780	SCV000602115	pathogenic	not provided	2016-06-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000507780	SCV000616839	pathogenic	not provided	2018-05-04	criteria provided, single submitter	clinical testing	This variant is denoted PTEN c.210-1G>A or IVS3-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 3 of the PTEN gene. This variant destroys a canonical splice acceptor site and has been demonstrated by RT-PCR studies to cause abnormal gene splicing, leading to skipping of exon 4 and subsequent nonsense-mediated mRNA decay (Celebi 2000, Agrawal 2005, Chen 2017). This variant has been reported in several individuals with features of PTEN Hamartoma Tumor syndrome, with at least one de novo observation (Celebi 2000, Mester 2012, Ngeow 2012, Iskandarli 2016, Chen 2017). Based on the current evidence, we consider this variant to be pathogenic.
Invitae	RCV000645050	SCV000766790	pathogenic	PTEN hamartoma tumor syndrome	2019-08-21	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Cowden syndrome (PMID: 11071384), and in a cohort of individuals with thyroid cancer and Cowden or Cowden-Like syndrome (PMID: 21956414). ClinVar contains an entry for this variant (Variation ID: 427616). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 11071384). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute	RCV000515846	SCV000579228	pathogenic	Cowden syndrome 1	2017-05-26	no assertion criteria provided	research