Submissions for variant NM_000314.8(PTEN):c.44G>A (p.Arg15Lys)

dbSNP: rs398123324

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000462758	SCV000840474	likely pathogenic	PTEN hamartoma tumor syndrome	2024-04-05	reviewed by expert panel	curation	NM_000314.8(PTEN):c.44G>A (p.Arg15Lys) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.1.0). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PM2_P: Absent in large sequenced populations (PMID 27535533). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (internal laboratory contributor: SCV000573362.4) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (<= -1.11) on a high throughput phosphatase assay (PMID:29706350).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462758	SCV000541593	pathogenic	PTEN hamartoma tumor syndrome	2021-07-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg15 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21417916, 16773562, 21659347, 24375884, 17942903, 25875300, 29706350). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this variant affects PTEN protein function (PMID: 25875300). This variant has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 404147). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 15 of the PTEN protein (p.Arg15Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine.
GeneDx	RCV000480861	SCV000573362	likely pathogenic	not provided	2017-03-13	criteria provided, single submitter	clinical testing	The R15K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, functional studies show that while R15K does not inhibit nuclear accumulation of PTEN, it does show severely diminished or completely abrogated phosphatase activity in vitro (Gil et al., 2015). The R15K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R15K variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and is located within the phosphatase domain and the N-terminal nuclear localization signal (Molinari et al., 2013; Gil et al., 2015). A missense variant in the same residue (R15S) has been reported in the Human Gene Mutation Database in association with Cowden syndrome (Nagy et al., 2011; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, R15K is a strong candidate for a pathogenic variant. However, the possibility it is a rare benign variant cannot be excluded.