ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121913293
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Total submissions: 15
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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 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-01 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 variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
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 2021-11-24 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763221 SCV000893848 pathogenic Macrocephaly-autism syndrome; Familial meningioma; Malignant tumor of prostate; VACTERL with hydrocephalus; Glioma susceptibility 2; PTEN hamartoma tumor syndrome; Cowden syndrome 1 2018-10-31 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
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

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