ClinVar Genomic variation as it relates to human health

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

For these reasons, this variant has been classified as Pathogenic. No functional studies have been performed to test the effects of this particular variant on PTEN protein stability, cellular location, or function. However, experimental studies have shown that other C-terminal truncating variants in this region affect the stability and function of the PTEN protein (PMID: 10468583, 10698513, 24905788), suggesting that deletion of this region of the PTEN protein is causative of disease. This variant is expected to result in the disruption of the last 68 amino acids (Tyr336-Val403) of the PTEN protein. This removes the C-terminal portion of the C2 domain, as well as the entire C-tail domain and PDZ binding domain (PMID: 25448482, 25336918, 24905788). This variant also deletes several critical phosphorylation sites within the C-tail domain, which are important for regulating PTEN protein stability and function (PMID: 12297295, 10866658, 11035045, 10468583). This variant has been observed in several individuals affected with PTEN-related disease (PMID: 20223021, 27477328, 28086757). This variant is also known as c.1006C>G and p.Tyr337X in the literature. ClinVar contains an entry for this variant (Variation ID: 481172). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PTEN gene (p.Tyr336*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acids of the PTEN protein.

The p.Y336* variant (also known as c.1008C>G), located in coding exon 8 of the PTEN gene, results from a C to G substitution at nucleotide position 1008. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This mutation has been reported in several individuals and/or families with clinical manifestations of the PTEN hamartoma tumor syndrome (PHTS) including Cowden or Cowden-like syndrome and Bannayan-Riley-Ruvalcaba syndrome (Rustad CF et al. Hered Cancer Clin Pract. 2006 Dec;4:177-85; Negishi Y et al. BMC Med. Genet. 2017 Jan;18:4; Chen HH et al. J. Allergy Clin. Immunol. 2017 Feb;139:607-620.e15). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. This alteration is also referred to as c.1006C>G in the literature.

The p.Tyr336* variant results in a premature stop codon and is expected to result in loss of protein function, a known disease mechanism for PTEN hamartoma tumor syndrome (PTHS, PMID: 20301661). This variant has been reported in multiple unrelated individuals with PTHS (PMID: 20223021, PMID: 29752200, PMID: 31336731).