10-87957852-G-C

Position:

• chr10-87957852-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.635-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.53

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 8, new splice context is: ttaaccatgcacatcctcAGttt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87957852-G-C is Pathogenic according to our data. Variant chr10-87957852-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87957852-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.635-1G>C		splice_acceptor_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1154-1G>C		splice_acceptor_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.44-1G>C		splice_acceptor_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.635-1G>C		splice_acceptor_variant, intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	May 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM2_Supporting+PS4_Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 29, 2023	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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2021	This variant causes a G to C nucleotide substitution at the -1 position of intron 6 of the PTEN gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA functional studies have reported the variant results in the use of cryptic splice sites (PMID: 16021145). This variant has been reported in individuals affected with PTEN Harmartoma Tumor Syndrome (PTHS; PMID: 10400993, 16021145, 20600018, 23335809, 24379037, 30898306) and was observed segregate with PTHS in one family (PMID: 16021145). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 21, 2023	The c.635-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 7 of the PTEN gene. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (Marsh DJ et al. Hum Mol Genet, 1999 Aug;8:1461-72; Mangas C et al. J Am Acad Dermatol, 2005 Aug;53:359-60; Heald B et al. Gastroenterology, 2010 Dec;139:1927-33; Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56; Bubien V et al. J Med Genet, 2013 Apr;50:255-63; Nizialek EA et al. Eur J Hum Genet, 2015 Nov;23:1538-43; Chen HJ et al. Hum Mutat, 2017 Oct;38:1372-1377; Pena-Couso L et al. Orphanet J Rare Dis, 2022 Feb;17:85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Chen HJ et al. Hum Mutat, 2017 Oct;38:1372-1377; Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23335809, 24379037, 25669429, 16021145, 9467011, 10400993, 11071384, 11174374, 20600018, 25527629, 28677221, 21194675, 34293297, 35227301, 25549896, 28526761, 19265751, 29020597) -
not provided, no classification provided	research	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change affects an acceptor splice site in intron 6 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 16021145, 35227301; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234446). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: 9
DS_AL_spliceai		0.98		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs876661024; hg19: chr10-89717609; COSMIC: COSV64296169;