Submissions for variant NM_000314.8(PTEN):c.70G>C (p.Asp24His)

dbSNP: rs786201995

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165524	SCV000216256	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-22	criteria provided, single submitter	clinical testing	The p.D24H pathogenic mutation (also known as c.70G>C), located in coding exon 1 of the PTEN gene, results from a G to C substitution at nucleotide position 70. The aspartic acid at codon 24 is replaced by histidine, an amino acid with similar properties. This mutation has been identified in two separate females with the following similar Cowden syndrome/PHTS characteristics: pathognomonic dermatological features, breast cancer, uterine cancer, macrocephaly, multinodular goiter, and renal cell carcinoma (Mester JL, Urology 2012 May; 79(5):1187.e1-7; Shuch B, J. Urol. 2013 Dec; 190(6):1990-8). This mutation was also found in multiple individuals meeting clinical criteria for Cowden Syndrome (Tan MH, Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Ngeow J et al. J. Clin. Oncol., 2014 Jun;32:1818-2; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). Further, an additional disease-causing mutation, p.D24N, has been described at this same codon. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523840	SCV001478147	likely pathogenic	Cowden syndrome 1	2020-12-15	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315436	SCV001506011	likely pathogenic	PTEN hamartoma tumor syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This variant disrupts the p.Asp24 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21194675, 22503188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 24 of the PTEN protein (p.Asp24His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features consistent with PTEN hamartoma tumor syndrome and/or PTEN-related conditions (PMID: 21194675, 24778394, 34308366; Invitae). ClinVar contains an entry for this variant (Variation ID: 186005). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798791	SCV005420884	likely pathogenic	Glioma	2024-10-04	criteria provided, single submitter	research	PM6,PM3(strong),PM2,PP3,PM5
GeneDx	RCV005051757	SCV005686053	pathogenic	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Reported in individuals with features of PTEN Hamartoma Tumor syndrome, including one apparently de novo observation (PMID: 34308366, 34374989, 22381246); Published functional studies demonstrate a damaging effect: impaired lipid phosphatase activity, aberrant cellular localization (PMID: 29706633, 29706350); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30626916, 21194675, 24778394, 33138866, 22381246, 23764071, 25669429, 24475377, 36453251, 29706633, 34308366, 34374989, 29706350)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678734	SCV000804906	pathogenic	not specified	2014-05-21	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785578	SCV000924151	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research