ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.202T>C (p.Tyr68His) (rs398123317)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000169864 SCV000222192 pathogenic not provided 2017-03-08 criteria provided, single submitter clinical testing The Y68H missense variant in the PTEN gene has previously been reported in association with PTEN-hamartoma tumor syndrome (for examples, see Marsh et al., 1998; Tsou et al., 1998; Nizialek et al., 2015). Functional studies demonstrate that Y68H significantly reduces phosphatase activity compared to wild-type, and that individuals harboring this variant have decreased levels of the PTEN protein compared to wild-type controls (Han et al., 2000; He et al., 2011). The Y68H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The Y68H substitution occurs at a position that is conserved across species, and located within the ATP binding motifs and phosphatase domain (Lobo et al., 2009; Molinari et al., 2014). Additionally, missense variants at this same codon (Y68N, Y68D, Y68C) have been reported in association with PTEN-hamartoma tumor syndrome (Loffeld et al., 2006; Lobo et al., 2009; Klein et al., 2013). Based on the currently available evidence, we consider Y68H to be pathogenic.
Ambry Genetics RCV000491290 SCV000580028 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-01 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Genetic Services Laboratory, University of Chicago RCV000499784 SCV000596622 likely pathogenic Cowden syndrome 1 2016-03-17 criteria provided, single submitter clinical testing
Invitae RCV000552740 SCV000645554 pathogenic PTEN hamartoma tumor syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 68 of the PTEN protein (p.Tyr68His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Cowden syndrome  (PMID: 20926450, 25669429, 19457929, 9600246), Bannayan-Riley-Ruvalcaba syndrome (PMID: 9467011), hemimegalencephaly (PMID: 25722288), and autism spectrum disorder (PMID: 25288137). ClinVar contains an entry for this variant (Variation ID: 189474). Experimental studies have shown that this missense change affects the subcellular localization of PTEN, and inhibits its protein phosphatase activity (PMID: 10866302, 20926450, 19457929). A different missense substitution at this codon (p.Tyr68Cys) has been determined to be pathogenic (PMID: 19457929, 26246517, 24778394, 21956414). 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.

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