ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.841C>G (p.Pro281Ala) (rs750705904)

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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 RCV000473403 SCV000930121 uncertain significance PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.841C>G (p.Pro281Ala) 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: 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. BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350)
Ambry Genetics RCV000163723 SCV000214297 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724763 SCV000232523 uncertain significance not provided 2015-04-17 criteria provided, single submitter clinical testing
Invitae RCV000473403 SCV000541623 uncertain significance PTEN hamartoma tumor syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 281 of the PTEN protein (p.Pro281Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 184466). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000724763 SCV000567275 uncertain significance not provided 2015-07-17 criteria provided, single submitter clinical testing This variant is denoted PTEN c.841C>G at the cDNA level, p.Pro281Ala (P281A) at the protein level, and results in the change of a Proline to an Alanine (CCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Pro281Ala 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 Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. PTEN Pro281Ala occurs at a position that is conserved across species and is located in the C2 domain. 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 Pro281Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000163723 SCV000691194 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-23 criteria provided, single submitter clinical testing

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