ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.493G>A (p.Gly165Arg) (rs587782603)

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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 RCV000690443 SCV001244250 pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.493G>A (p.Gly165Arg) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2) PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302) PM2: Absent in large sequenced populations (PMID 27535533). 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. (PMID 23335809, internal laboratory contributor SCV000617324.2)
Ambry Genetics RCV000491530 SCV000580051 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-08 criteria provided, single submitter clinical testing The p.G165R variant (also known as c.493G>A) is located in coding exon 6 of the PTEN gene. The glycine at codon 165 is replaced by arginine, an amino acid with dissimilar properties. This variant is located in the PTP catalytic domain. In two functional studies, in vitro phosphatase activity was severely reduced compared to the wild type PTEN protein and was similar to a catalytic dead control (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Han SY et al. Cancer Res., 2000 Jun;60:3147-51). Two other alterations at this position, p.G165E and p.G165V, have been observed to result in reduced in vivo activity in yeast (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). In one study of gene expression profiles in breast cancers, the p.G165R variant was detected in the germline of an individual with breast cancer at 59 years and meeting a medical genetics diagnosis of suspected Cowden syndrome (Banneau G et al. Breast Cancer Res. 2010;12(4):R63). This alteration has also been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (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). 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.
GeneDx RCV000522601 SCV000617324 pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing The G165R variant in the PTEN gene was observed in at least one individual with breast cancer, and in one individual undergoing clinical testing of the PTEN gene (Banneau et al., 2010; Pilarksi et al., 2011). Functional studies show that G165R significantly decreases PTEN phosphatase activity (Myers et al., 1997; Han et al., 2000). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. This substitution occurs at a position that is conserved across species and is located in the phosphatase domain (Molinari et al., 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000690443 SCV000818127 likely pathogenic PTEN hamartoma tumor syndrome 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 165 of the PTEN protein (p.Gly165Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Cowden syndrome, and in one individual affected with either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 20712882, 21194675, 21659347). ClinVar contains an entry for this variant (Variation ID: 428256). Experimental studies have shown that this missense change disrupts the phosphatase activity of the PTEN protein (PMID: 10866302, 9256433). 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.

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