Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000704361 | SCV000833306 | pathogenic | PTEN hamartoma tumor syndrome | 2023-08-10 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 14675182, 17942903, 21828076, 24498881, 25527629). 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: 580731). This missense change has been observed in individual(s) with PTEN hamartoma syndrome (PMID: 14675182, 17526800, 24498881, 25527629). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 48 of the PTEN protein (p.Asn48Lys). |
| Ambry Genetics | RCV001011640 | SCV001171986 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-30 | criteria provided, single submitter | clinical testing | The p.N48K pathogenic mutation (also known as c.144C>A), located in coding exon 2 of the PTEN gene, results from a C to A substitution at nucleotide position 144. The asparagine at codon 48 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in individuals reported to meet clinical diagnostic criteria for Cowden syndrome (Vega A et al. J. Invest. Dermatol. 2003 Dec;121:1356-9; Morse CB et al. Gynecol. Oncol. Rep. 2015 Apr;12:13-6; Shon W et al. Br J Dermatol, 2014 May;170:1201-4). This alteration was reported as de novo in a 7-year-old child with clinical features of PTEN hamartoma tumor syndrome (Lachlan KL et al. J. Med. Genet. 2007 Sep;44:579-85). This alteration was also reported in several individuals suspected of having Cowden syndrome (Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Nieuwenhuis MH et al. Fam. Cancer 2014 Mar;13:57-63; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). In a functional study using a yeast-based assay, this variant demonstrated severely reduced phosphatase activity when compared to wild type PTEN and was similar to the catalytic dead control (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). In several studies, this variant showed normal protein expression that was comparable to wild type PTEN, but demonstrated reduced PTEN function (Vega A et al. J. Invest. Dermatol. 2003; Andrés-Pons A et al. Cancer Res. 2007 Oct;67:9731-9 Dec;121:1356-9; Spinelli L et al. J. Med. Genet. 2015 Feb;52:128-34). 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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003453494 | SCV004188772 | likely pathogenic | Cowden syndrome 1 | 2023-09-26 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 14675182, 25527629]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14675182, 17526800, 21659347, 25527629]. |
| Baylor Genetics | RCV003465631 | SCV004206666 | pathogenic | Glioma susceptibility 2 | 2023-09-13 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV000704361 | SCV005400415 | pathogenic | PTEN hamartoma tumor syndrome | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Cowden syndrome 1 (MIM#158350). Loss of function is the mechanism for null variants while missense variants have been demonstrated to exert either a loss of function or dominant-negative mechanism (PMID: 20301661). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (PMID: 20301661). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated protein-tyrosine phosphatase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant and an alternate nucleotide subsitution resulting in the same amino acid change have been reported five times as pathogenic, three times as likely pathogenic (ClinVar), in four individuals with Cowden Syndrome and has been identified in individuals with PTEN-related features in two cohort studies (PMID: 26076150, 14675182, 17526800, 35971940, 23934601, 25669429). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cell lines have demonstrated that this variant impairs the ability of the PTEN protein to suppress AKT phosphorylation when compared with wild-type protein (PMID: 25527629, 14675182). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |