Submissions for variant NM_000314.8(PTEN):c.613A>G (p.Met205Val)

gnomAD frequency: 0.00001  dbSNP: rs776763121

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000458840	SCV000541592	uncertain significance	PTEN hamartoma tumor syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 205 of the PTEN protein (p.Met205Val). This variant is present in population databases (rs776763121, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 404146). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 27514801, 29706350, 29785012). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Ambry Genetics	RCV000568825	SCV000671714	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	The p.M205V variant (also known as c.613A>G), located in coding exon 6 of the PTEN gene, results from an A to G substitution at nucleotide position 613. The methionine at codon 205 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56). This variant has also been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). In one Japanese case-control study, this variant was not identified in any female breast cancer cases and was found in 1/11241 controls (Momozowa Y et al. Nat Commun 2018 10;9(1):4083). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). This variant demonstrated possibly low 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.
Counsyl	RCV000662536	SCV000785111	uncertain significance	Cowden syndrome 1	2017-04-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000458840	SCV000838421	uncertain significance	PTEN hamartoma tumor syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000568825	SCV000906733	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 205 of the PTEN protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in the literature in two individuals affected with, or suspected of having, Cowden syndrome (PMID: 21194675, 25669429). In an international breast cancer case-control meta-analysis, this variant has been detected in 2/60466 cases and absent in 53461 controls (PMID: 33471991). This variant has also been identified in 5/281840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV002466500	SCV002762513	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least two individuals with features of Cowden syndrome (Tan et al., 2011; Nizialek et al., 2015); Published functional studies demonstrate possibly wildtype-like protein stability (Matreyek et al., 2018); This variant is associated with the following publications: (PMID: 25669429, 25980754, 21194675, 18626510, 29785012, 31006514, 29663862, 34268892)
Myriad Genetics, Inc.	RCV000662536	SCV004019959	uncertain significance	Cowden syndrome 1	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003463842	SCV004206661	uncertain significance	Glioma susceptibility 2	2023-10-05	criteria provided, single submitter	clinical testing