Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001047913 | SCV001211897 | uncertain significance | PTEN hamartoma tumor syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 171 of the PTEN protein (p.Gln171Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 24375884). ClinVar contains an entry for this variant (Variation ID: 844941). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 29785012, 32350270). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002348382 | SCV002645865 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-07-06 | criteria provided, single submitter | clinical testing | The p.Q171E variant (also known as c.511C>G), located in coding exon 6 of the PTEN gene, results from a C to G substitution at nucleotide position 511. The glutamine at codon 171 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in two related individuals: a 5-year-old female and her sister, both with macrocephaly, developmental delays and prominent perivascular spaces (Vanderver A et al. Am. J. Med. Genet. A, 2014 Mar;164A:627-33). Functional assays demonstrated reduced phosphatase activity for p.Q171E compared to wild type PTEN (Mighell TL et al. Am. J. Hum. Genet., 2018 05;102:943-955; Post KL et al. Nat Commun, 2020 Apr;11:2073). Based on internal structural analysis using published crystal structures, p.Q171E is likely to disrupt important interactions between the TI loop and substrates (Lee JO et al. Cell, 1999 Oct;99:323-34; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42; Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |