ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Gln214*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 7827). This premature translational stop signal has been observed in individual(s) with a diagnosis or suspicion of Cowden syndrome (PMID: 9832032, 10606430, 17954274, 21659347, 23160955, 27477328, 28086757). In at least one individual the variant was observed to be de novo.

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

The p.Q214* pathogenic mutation (also known as c.640C>T), located in coding exon 7 of the PTEN gene, results from a C to T substitution at nucleotide position 640. This changes the amino acid from a glutamine to a stop codon within coding exon 7. This alteration was confirmed as a de novo mutation in a patient meeting clinical criteria for Bannayan-Riley-Ruvalcaba (BRR) syndrome (Longy M et al. J. Med. Genet. 1998 Nov;35:886-9). This mutation has also been seen in multiple patients with Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol. 2002 Apr;118:639-44; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Kato K et al. Brain Dev. 2018 Sep;40(8):678-684) and in individuals with autism (O'Roak BJ et al. Science 2012 Dec;338:1619-22; Kosmicki J et al. Nat. Genet. 2017 Apr;49(4):504-510). Tate et al. report this mutation in an individual with hepatic angiosarcoma, breast and pharyngeal cancer, thyroid clear cell adenoma, and uterine leiomyoma (Tate G et al. Cancer Genet. Cytogenet. 2007 Oct;178:160-2). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27477328, 12560928, 9832032, 28086757, 21659347, 17954274, 10606430, 11918710, 27059323, 23160955, 24664487, 26197069, 21194675, 10232405, 28152038, 28191890, 34312540, 29752200, 35227301)

Patient, a 4 year-old girl, showed mild developmental delay and dysmorphic facial features. Her last head circumference was 57 cm (+4.1SD). The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated.