ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.406T>C (p.Cys136Arg) (rs786201044)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162428 SCV000212775 pathogenic Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing The p.C136R pathogenic mutation (also known as c.406T>C), located in coding exon 5 of the PTEN gene, results from a T to C substitution at nucleotide position 406. The cysteine at codon 136 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was described as a de novo mutation in a Japanese patient with Cowden disease (Kubo Y et al. Br. J. Dermatol. 2000 Jun;142(6):1100-5). In one PTEN Hamartoma Tumor Syndrome (PHTS) family, this mutation segregated with disease in a mother and her two daughters. Clinical features included macrocephaly and thyroid lesions (follicular carcinoma and adenoma) in all three individuals, breast cancer in the mother, vertebral hemangioma in one daughter, and cortical dysplasia in the other daughter (Jenny B et al. J. Neurosurg. 2007 Oct;107(4 Suppl):307-13; Venturini G et al. Ophthalmology 2012 Apr;119(4):857-64). This mutation has also been observed in other individuals with PHTS (Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Galatola M et al. BMC Med. Genet., 2012 Apr;13:28) including those with neurological features of PHTS such as autism and developmental delay (He X et al. Cancer Res. 2013 May;73(10):3029-40). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212881 SCV000222112 pathogenic not provided 2021-06-09 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: impaired phosphatase activity, reduced PTEN protein levels and stability (He et al., 2013; Mighell et al., 2018; Matreyek et al., 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21659347, 31965297, 28380455, 29663862, 23335809, 32601921, 17941496, 22281088, 10848731, 27148581, 25461771, 23886400, 22520842, 15211648, 18558293, 23475934, 21343951, 20600018, 24778394, 21194675, 26376867, 31006514, 29785012, 19457929, 24475377, 29706350)
Invitae RCV000463307 SCV000541633 pathogenic PTEN hamartoma tumor syndrome 2020-09-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 136 of the PTEN protein (p.Cys136Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) . This variant has been observed in individuals with Cowden syndrome (PMID: 10848731, 20600018, 24778394), PTEN hamartoma tumor syndrome (PMID: 21343951, 22520842, 23335809), and Bannayan-Riley-Ruvalcaba syndrome (PMID: 23886400, 21659347). ClinVar contains an entry for this variant (Variation ID: 183726). Experimental studies have shown that this variant affects the stability of the PTEN protein (PMID: 23475934). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587477 SCV000696534 pathogenic Cowden syndrome 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The PTEN c.406T>C (p.Cys136Arg) variant located in the Protein-tyrosine phosphatase-like domain involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121500 control chromosomes. Multiple publications have cited the variant in affected indivdiuals diagnosed with Cowden Syndrome, BRRS, and PHTS, which was found to cosegregate with disease in multiple families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Functional studies have demonstrated an impact of this variant on protein stability leading to increased proteasome activity which has been reported as a hallmark of human cancers. Taken together, this variant is classified as pathogenic.
McDonnell Genome Institute,Washington University in St. Louis RCV000202582 SCV000257334 pathogenic Acute megakaryoblastic leukemia; Mediastinal germ cell tumor 2015-10-22 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785388 SCV000923959 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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