Submissions for variant NM_000314.8(PTEN):c.16A>G (p.Lys6Glu)

dbSNP: rs1589596143

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000798296	SCV002576554	pathogenic	PTEN hamartoma tumor syndrome	2021-06-04	reviewed by expert panel	curation	PTEN c.16A>G (p.Lys6Glu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS2_VS: One proven plus two assumed de novo observations in a patient with the disease and no family history. (internal laboratory contributor(s) SCV001369131.2, SCV001819316.1) PS4_M: Probands with phenotype specificity score of 2-3.5. (internal laboratory contributor(s) SCV001819316.1) PM2: Absent in large sequenced populations (PMID 27535533). 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_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 32366478, PMID 32350270, PMID 29706350)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798296	SCV000937903	uncertain significance	PTEN hamartoma tumor syndrome	2022-10-12	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 6 of the PTEN protein (p.Lys6Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function. ClinVar contains an entry for this variant (Variation ID: 644390). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 24375884). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV001012790	SCV001173290	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The p.K6E variant (also known as c.16A>G), located in coding exon 1 of the PTEN gene, results from an A to G substitution at nucleotide position 16. The lysine at codon 6 is replaced by glutamic acid, an amino acid with similar properties. This alteration was reported in an 11 month old female with macrocephaly and developmental delay with posterior periventricular multifocal white matter abnormalities and enlarged perivascular spaces with CSF isointense signal (Vanderver A et al. Am. J. Med. Genet. A, 2014 Mar;164A:627-33). This alteration was also reported in a patient with developmental and intellectual delay, autism spectrum disorder and macrocephaly before the age of 19 (Baran JA et al. Horm Res Paediatr, 2020 Apr;93:634-642). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was hypomorphic (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This variant demonstrated wildtype-like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198257	SCV001369131	likely pathogenic	Familial meningioma	2019-05-31	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
GeneDx	RCV001585722	SCV001819316	pathogenic	not provided	2020-12-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased phosphatase activity and wild type-like protein stability (Mighell et al., 2018, Matreyek et al., 2018). Additional functional studies demonstrate complete and partial loss of function when compared to wild type through multiple differing assays (Post et al., 2020, Chao et al., 2020); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32366478, 32350270, 24375884, 29785012, 29706350, 27514801)