10-87957850-C-G

Variant names:

• chr10-87957850-C-G
• rs1085308056
• NM_000314.8:c.635-3C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM6_Strong PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA645294060/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.42
• Publications: 3 publications found

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.635-3C>G		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1154-3C>G		splice_region_variant, intron_variant	Intron 7 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.44-3C>G		splice_region_variant, intron_variant	Intron 6 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.635-3C>G		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:4

Jun 04, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 01, 2017

Herman Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2023

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: 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) -

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with PTEN hamartoma tumour syndrome and/or PTEN-related conditions (PMID: 19265751, 23335809, 28526761, 35278038, 36974006). In at least one individual the variant was observed to be de novo. This variant is also known as IVS6-3C>G. ClinVar contains an entry for this variant (Variation ID: 427599). Variants that disrupt 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cowden syndrome 1 Pathogenic:1

May 14, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19265751, 28526761, 38546160, Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 29, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		4.4
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.85		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1085308056; hg19: chr10-89717607; COSMIC: COSV64301307;