Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000698131 | SCV000826774 | pathogenic | PTEN hamartoma tumor syndrome | 2024-04-06 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 252 of the PTEN protein (p.Asp252Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 25288137, 25669429; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 575811). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 27514801, 29706350, 29785012). This variant disrupts the p.Asp252 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23335809, 25527629, 26579216, 29373119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002388286 | SCV002670873 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-03-04 | criteria provided, single submitter | clinical testing | The p.D252V variant (also known as c.755A>T), located in coding exon 7 of the PTEN gene, results from an A to T substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by valine, an amino acid with highly dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee JO, et al. Cell 1999 Oct; 99(3):323-34). This alteration was described in a cohort of individuals with autism spectrum disorder (Frazier TW, et al. Mol. Psychiatry 2015 Sep; 20(9):1132-8). Additionally, another amino acid change at the same codon (p.D252G) has been identified in a child with an autism spectrum disorder and macrocephaly as well as in a series suspected-PHTS patients (Spinelli L, et al. J. Med. Genet. 2015 Feb; 52(2):128-34. Pilarski R et al, J. Med. Genet. 2011 Aug; 48(8):505-12. Butler MG et al, J. Med. Genet. 2005 Apr; 42(4):318-21). The p.D252V variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0005% (greater than 200000 alleles tested) in our clinical cohort. This variant was detected in an individual meeting diagnostic criteria for Cowden syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479201 | SCV004223706 | likely pathogenic | Cowden syndrome | 2023-11-13 | criteria provided, single submitter | clinical testing | Variant summary: PTEN c.755A>T (p.Asp252Val) results in a non-conservative amino acid change in the encoded protein sequence. A different variant at the same codon, c.755A>G (p.Asp252Gly) has been classified as Likely pathogenic/pathogenic supporting the critical relevance of the Aspartate 252 residue to PTEN protein function. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251422 control chromosomes. c.755A>T has been reported in the literature in individuals affected with autism spectrum disorders, PTEN-hamartoma syndrome, Cowden syndrome and in settings of Thyroid nodules (example, Frazier_2015, Kim_2022, Yehia_2022, Nizialek_2015, Quaytman_2022). These data indicate that the variant may be associated with disease. Several studies have reported an impact on PTEN-function, however, these were not weighted in the context of this evaluation. The following publications have been ascertained in the context of this evaluation (PMID: 25288137, 34492006, 36175890, 29785012, 29706350, 25669429, 31232187, 35723418, 31427284, 25527629, 35241692). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |