Submissions for variant NM_000314.8(PTEN):c.517C>T (p.Arg173Cys)

gnomAD frequency: 0.00001  dbSNP: rs121913293

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PTEN Variant Curation Expert Panel	RCV000490574	SCV000840496	pathogenic	PTEN hamartoma tumor syndrome	2017-10-18	reviewed by expert panel	curation	PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10) PS3: Phosphatase activity <50% of wild type. (PMID 10866302) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801) PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360) 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.
GeneDx	RCV000169890	SCV000222220	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han 2000, Mighell 2018); Not observed 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: 17526800, 9635567, 29874181, 31006514, 32369273, 31216405, 10866302, 24778394, 22628360, 27481051, 9619835, 10746673, 10812170, 25669429, 28475857, 29663862, 20600018, 29706350, 26582918, 24475377, 33509259, 31594918, 30787465, 17526801)
Ambry Genetics	RCV000218276	SCV000273596	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-23	criteria provided, single submitter	clinical testing	The p.R173C variant (also known as c.517C>T), located in coding exon 6 of the PTEN gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature in multiple individuals with clinical characteristics of Cowden syndrome or Cowden syndrome&ndash;like disease (Hopman SM et al. Am. J. Med. Genet. A 2012 Jul;158A(7):1719-23; Lachlan KL et al. J. Med. Genet. 2007 Sep;44(9):579-85; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32(17):1818-24; Tan WH et al. J. Med. Genet. 2007 Sep;44(9):594-602; Tatton-Brown K et al. Am. J. Hum. Genet., 2017 May;100:725-736; Tang VT et al. Circ Genom Precis Med, 2018 01;11:e001966). This alteration has also been reported as de novo in individuals with clinical features of PTEN hamartoma tumor syndrome (PHTS) (Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Hopman SM et al. Am. J. Med. Genet. A, 2012 Jul;158A:1719-23). In addition, one functional study demonstrated that the p.R173C mutant resulted in absent phosphatase activity (Han SY et al. Cancer Res. 2000 Jun;60(12):3147-51). 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.
Herman Laboratory, Nationwide Children's Hospital	RCV000490574	SCV000579278	pathogenic	PTEN hamartoma tumor syndrome	2017-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV000490574	SCV000645594	pathogenic	PTEN hamartoma tumor syndrome	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 173 of the PTEN protein (p.Arg173Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN Hamartoma Tumor Syndrome (PMID: 17526800, 22628360, 24778394, 25669429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189500). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002478525	SCV000893848	pathogenic	Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; Glioma susceptibility 2; Cowden syndrome 1	2021-10-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000850588	SCV000992811	pathogenic	Macrocephaly-autism syndrome; VACTERL with hydrocephalus; Cowden syndrome 1	2017-12-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218276	SCV002052545	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 173 of the PTEN protein. The amino acid residue is highly conserved in PTEN, a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. Functional studies have shown this variant to be defective for PTEN phosphatase activity (PMID: 10866302). This variant has been reported in individuals with clinical characteristics consistent with Cowden or Cowden-like syndrome (PMID: 17526800, 17526801, 21194675, 22628360, 24778394, 28475857, 28526761, 29874181), including two individuals in which it is assumed to have occurred de novo (PMID: 17526800, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD).
DASA	RCV001813763	SCV002061176	pathogenic	Cowden syndrome 1	2022-01-05	criteria provided, single submitter	clinical testing	The c.517C>T;p.(Arg173Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:189500; PMID: 28526761; 28475857; 25669429; 25157968; 24778394; 17526800; 17526801; 22628360) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 10866302) - PS3_supporting. This variant is not present in population databases (rs121913293, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 428258) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17526800; 22628360) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001813763	SCV002549862	pathogenic	Cowden syndrome 1	2022-07-12	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4, PM1, PM5, PM2_SUP, PP3
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273970	SCV002559024	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490574	SCV004014738	pathogenic	PTEN hamartoma tumor syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The PTEN c.517C>T (p.Arg173Cys) missense variant has been reported in a heterozygous state in at least six individuals with PTEN hamartoma tumor syndrome, including in four variably affected individuals from one family across two generations (PMID: 17526801; 17526800; 22628360). The variant is assumed to have occurred de novo in at least two affected individuals (PMID: 17526800; 22628360). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Studies of recombinant variant protein demonstrate that p.Arg173Cys results in a reduction in phosphatase activity when compared to wildtype (PMID: 10866302). This variant was identified in a de novo state. Based on the available evidence, the c.517C>T (p.Arg173Cys) variant is classified as pathogenic for PTEN hamartoma tumor syndrome.
Database of Curated Mutations (DoCM)	RCV000445192	SCV000505649	likely pathogenic	Neoplasm of brain	2015-07-14	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678738	SCV000804910	pathogenic	not specified	2012-02-12	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000169890	SCV001918789	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000169890	SCV001954774	pathogenic	not provided		no assertion criteria provided	clinical testing