ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.284C>T (p.Pro95Leu) (rs786204856)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000490609 SCV000930116 pathogenic PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.284C>T (p.Pro95Leu) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 21828076, PMID 29706350) PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID 26957) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor ClinVar Organization ID 26957)
Herman Laboratory,Nationwide Children's Hospital RCV000490609 SCV000579266 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV000490609 SCV000829973 likely pathogenic PTEN hamartoma tumor syndrome 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 95 of the PTEN protein (p.Pro95Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Cowden syndrome and/or PTEN hamartoma tumor syndrome (PMID: 21194675, 21659347, 28526761, Invitae). ClinVar contains an entry for this variant (Variation ID: 189403). Experimental studies have shown that this missense change affects PTEN PIP3 phosphatase activity (PMID: 21828076, 29706350). 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.
Ambry Genetics RCV001016786 SCV001177782 pathogenic Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing The p.P95L pathogenic mutation (also known as c.284C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 284. The proline at codon 95 is replaced by leucine, an amino acid with similar properties. This variant has been identified in children meeting clinical diagnostic criteria for PTEN hamartoma tumor syndrome (PHTS) and one of the cases was assumed to be de novo since there was a lack of family history; however, confirmation of paternity and maternity was not performed (Ambry internal data; Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478). This alteration has also been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Heald B et al. Gastroenterology, 2010 Dec;139:1927-33; Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Pilarski R et al. J. Med. Genet., 2011 Aug;48:505-12; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). Experimental functional studies demonstrated severely reduced phosphatase activity when compared to wild type PTEN for this variant (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42; Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955). Other alterations at the same amino acid position, p.P95A and p.P95T, have been reported as likely pathogenic based on identification in individuals meeting clinical criteria for PHTS and internal structural assessments. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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