ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1093G>A (p.Val365Ile) (rs758542021)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000228413 SCV000930120 uncertain significance PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.1093G>A (p.Val365Ile) is currently classified as a variant of uncertain significance 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). PM2: Present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (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. BS3: Missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. (PMID 29785012, 29706350)
Invitae RCV000228413 SCV000284581 uncertain significance PTEN hamartoma tumor syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 365 of the PTEN protein (p.Val365Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 237639). This variant has been reported not to substantially affect PTEN protein function (PMID: 29706350, 29785012). 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.
GeneDx RCV000485218 SCV000566883 uncertain significance not provided 2015-06-15 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1093G>A at the cDNA level, p.Val365Ile (V365I) at the protein level, and results in the change of a Valine to an Isoleucine (GTA>ATA). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism, but has been reported as a somatic variant in cervical adenocarcinoma (COSMIC, Holway 2000). PTEN Val365Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PTEN Val365Ile occurs at a position that is conserved across species and is not located in a known functional domain (Nguyen 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether PTEN Val365Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561607 SCV000671741 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000561607 SCV000686270 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing
Counsyl RCV000662585 SCV000785211 uncertain significance Cowden syndrome 1 2017-06-02 criteria provided, single submitter clinical testing

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