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

dbSNP: rs1085308056

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000490589	SCV001244248	likely pathogenic	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(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 criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2_P: Absent in large sequenced populations (PMID:27535533). PM6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID:19265751) PP3: SpliceAI predicts a splicing impact. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:35278038)
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	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. 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. 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). This variant is not present in population databases (ExAC no frequency). 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.
Laboratory for Molecular Medicine, Mass General Brigham 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