Submissions for variant NM_000314.8(PTEN):c.968del (p.Asn323fs)

dbSNP: rs121913291

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000809184	SCV000949326	pathogenic	PTEN hamartoma tumor syndrome	2020-01-07	criteria provided, single submitter	clinical testing	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 81 amino acids (Ala323-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 an individual with clinical features of Cowden syndrome (PMID: 20600018). 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.Asn323Metfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acids of the PTEN protein.
Ambry Genetics	RCV001019622	SCV001181004	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-12	criteria provided, single submitter	clinical testing	The c.968delA pathogenic mutation, located in coding exon 8 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 968, causing a translational frameshift with a predicted alternate stop codon (p.N323Mfs*21). This alteration has been reported in two separate studies evaluating probands meeting relaxed International Cowden Consortium PHTS criteria (Heald B et al. Gastroenterology 2010 Dec;139(6):1927-33; Nizialke EA et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43). This mutation, designated as 967delA, was also detected in a mosaic state in an individual who presented with multiple colonic ganglioneuromas, tongue papules, macrocephaly, thyroid goiter, and suspected trichilemmoma (Gammon A et al. Clin. Genet. 2013 Dec;84(6):593-5). 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.
Myriad Genetics, Inc.	RCV003453693	SCV004189527	pathogenic	Cowden syndrome 1	2023-10-03	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Department Of Pathology & Laboratory Medicine, University Of Pennsylvania	RCV003448983	SCV004176802	pathogenic	Malignant lymphoma, large B-cell, diffuse	2023-12-04	no assertion criteria provided	clinical testing	Post-initial therapy specimen.