ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.802-3T>A (rs587780712)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000123051 SCV001335274 uncertain significance PTEN hamartoma tumor syndrome 2020-03-23 reviewed by expert panel curation PTEN c.802-3T>A (IVS7-3T>A) 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 BP4: Intronic variant where at least 2 out of 3 in silico models predict no splicing impact.
Invitae RCV000123051 SCV000166346 uncertain significance PTEN hamartoma tumor syndrome 2019-04-03 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein, but it affects a nucleotide within the consensus splice site of the intron. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 135912). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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.
Ambry Genetics RCV000130646 SCV000185525 likely benign Hereditary cancer-predisposing syndrome 2020-04-03 criteria provided, single submitter clinical testing In silico models in agreement (benign);RNA Studies
Counsyl RCV000662445 SCV000784913 uncertain significance Cowden syndrome 1 2017-02-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193509 SCV001362395 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: PTEN c.802-3T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 204652 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.802-3T>A in individuals affected with Cowden Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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