ClinVar Miner

Submissions for variant NM_000314.8(PTEN):c.635-3C>G (rs1085308056)

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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 RCV000490589 SCV001244248 likely pathogenic PTEN hamartoma tumor syndrome 2019-11-22 reviewed by expert panel curation PTEN c.635-3C>G (IVS6-3C>G) meets criteria to be classified as likely 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). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (PMID 19265751) PP3: At least 2 out of 3 in silico models predict a splicing impact. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 19265751)
Herman Laboratory,Nationwide Children's Hospital RCV000490589 SCV000579285 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491647 SCV000579957 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing The c.635-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 7 in the PTEN gene. This intronic variant has been reported in at least two independent PTEN hamartoma tumour syndrome cohorts (Varga EA et al. Genet Med. 2009 Feb;11(2):111-7; Bubien V, et al. J. Med. Genet. 2013 Apr; 50(4):255-63). In one study, this alteration was identified as a de novo finding in a 6 year old boy with autism spectrum disorder, macrocephaly, and other dysmorphic features. Two years later this child was reevaluated and found to have freckling of the glans penis suggesting a diagnosis of Bannayan-Riley-Ruvalcaba syndrome (BRRS). Authors referred to this alteration as IVS6-3C>G (Varga EA et al. Genet Med. 2009 Feb;11(2):111-7). This nucleotide position is highly conserved in available vertebrate species. Using the MaxEntScan3' splice site prediction tool, this alteration is predicted to have a significant effect on the native splice acceptor site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to weaken the native splice acceptor site (Desmet FO et al. Nucleic Acids Res. 2009 May;37(9):e67). However, direct evidence in regards to impact on the native splice acceptor site is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000490589 SCV000812483 uncertain significance PTEN hamartoma tumor syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change falls in intron 6 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 been observed to be de novo in an individual affected with PTEN hamartoma tumour syndrome (PMID: 28526761, 19265751), and was identified in an individual affected with Cowden syndrome (PMID: 23335809). This variant is also known as IVS6-3C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 427599). 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 may disrupt the consensus 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000490589 SCV001736712 likely pathogenic PTEN hamartoma tumor syndrome 2021-06-04 criteria provided, single submitter clinical testing The c.635-3C>G variant in PTEN has been previously reported in at least 2 individuals with features of PTEN hamartoma syndrome, including 1 individual in whom the variant was reported de novo (Varga 2009 PMID:19265751, Bubien 2013 PMID: 23335809, Hansen Kiss 2017 PMID: 28526761). This variant was absent from large population studies. This variant is located in the 3' splice region. Computational tools predict a splicing impact. Of note, one study performed reverse transcriptase PCR on lymphocytes from one of the probands harboring this variant but no altered splicing was uncovered (Varga 2009 PMID:19265751). Moreover, this variant was classified as likely pathogenic on Nov. 22, 2019 by the ClinGen-approved PTEN variant curation expert panel (Variation ID 427599). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PTEN hamartoma syndrome. ACMG/AMP criteria applied: PS4_Moderate, PM6, PM2_Supporting, PP3.
MutSpliceDB: a database of splice sites variants effects on splicing,NIH RCV000853544 SCV000996514 not provided not provided no assertion provided in vivo

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