ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.203A>G (p.Tyr68Cys) (rs876660634)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215167 SCV000278224 pathogenic Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing The p.Y68C alteration (also known as c.203A>G), located in coding exon 3 of the PTEN gene, results from an A to G substitution at nucleotide position 203. The tyrosine at codon 68 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was previously reported in a cohort of individuals with Cowden syndrome or Cowden-like disease in a woman diagnosed with thyroid cancer at age 46 and breast cancer at age 57 (Ngeow J, J. et al. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2063-71; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32(17):1818-24). In addition, this alteration was reported in a 5 year old boy with macrocephaly, mild developmental delay and immunodeficiency, and was inherited from his macrocephalic father. Functional analyses in isolated T cells from this individual showed reduced PTEN protein expression and increased AKT and S6 phosphorylation in peripheral blood T cells (Browning MJ et al. J. Med. Genet. 2015 Aug). In addition, this alteration is located in a putative ATP-biding site, and is associated with an increase in PTEN nuclear localization compared to wildtype controls (Lobo GP et al. Hum. Mol. Genet. 2009 Aug;18(15):2851-62). A similar alteration, p.Y68D, was reported in a boy with a clinical diagnosis of proteus syndrome and his mother with clinical features of Cowden syndrome (Loffeld A et al. Br. J. Dermatol. 2006;154 (6):1194-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Invitae RCV000690989 SCV000818724 pathogenic PTEN hamartoma tumor syndrome 2019-04-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 68 of the PTEN protein (p.Tyr68Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Cowden syndrome (PMID: 19457929, 24778394, 26246517, 21956414). ClinVar contains an entry for this variant (Variation ID: 233777). Experimental studies have shown that this missense change affects the subcellular localization of PTEN, and inhibits its protein phosphatase activity (PMID: 19457929, 26246517). Other missense substitutions at this codon (p.Tyr68His and p.Tyr68Asp) have been reported in individuals affected with Cowden syndrome and have been determined to be pathogenic or likely pathogenic (PMID: 25669429, 9600246, 16704655, 20926450, 19457929). This suggests that the tyrosine residue is critical for PTEN protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735377 SCV000854532 pathogenic Autistic disorder; Global developmental delay; Seizures; Cognitive impairment; Cerebral visual impairment; Microcephaly; Developmental regression; Infantile spasms criteria provided, single submitter clinical testing
Baylor Genetics RCV001332358 SCV001524660 pathogenic Cowden syndrome 1 2020-10-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001551732 SCV001772302 pathogenic not provided 2019-10-04 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: aberrant phosphatase activity and cellular localization (Mighell 2018, Lobo 2009); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30755392, 29706350, 29296277, 25669429, 9288766, 30287823, 19457929, 21956414, 24778394, 26246517)

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