Submissions for variant NM_000314.8(PTEN):c.408T>G (p.Cys136Trp)

dbSNP: rs869312776

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210082	SCV000266123	likely pathogenic	Cowden syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853360	SCV002159000	uncertain significance	PTEN hamartoma tumor syndrome	2022-03-10	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 136 of the PTEN protein (p.Cys136Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224543). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant disrupts the p.Cys136 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9735393, 10848731, 10866302, 20600018, 21659347, 22520842, 23335809, 23475934, 23886400, 24778394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV003165516	SCV003864655	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.C136W variant (also known as c.408T>G), located in coding exon 5 of the PTEN gene, results from a T to G substitution at nucleotide position 408. The cysteine at codon 136 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration has been identified in individuals meeting clinical criteria of Cowden Syndrome (Ambry internal data; Shirts BH et al. Genet Med, 2016 Oct;18:974-81). This variant demonstrated possible wild-type like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). Another alteration at the same codon, p.C136Y (c.407G>A), has been described in individuals meeting clinical criteria for PTEN Hamartoma Tumor Syndrome (PHTS)/Cowden syndrome (CS) (Sarquis MS et al. Am. J. Hum. Genet., 2006 Jul;79:23-30; Heald B et al. Gastroenterology, 2010 Dec;139:1927-3; Ngeow J et al. J Clin Endocrinol Metab. 2011 Dec;96(12):E2063-71; Tan MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV003228913	SCV003926429	pathogenic	not provided	2023-05-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as the C136W variant was associated with reduced cellular lipid phosphatase activity in a humanized yeast model (Mighell et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24425785, 35338148, 33152507, 26845104, 29785012, 29706350, 24475377, 19457929, 9735393, 20600018, 23886400, 23335809, 23475934)