rs1060500124

chr10-87933252-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_000314.8(PTEN):c.492+2del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 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_donor
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09818482 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of -21, new splice context is: gaaGTaagg. Cryptic site results in inframe 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-87933252-GT-G is Pathogenic according to our data. Variant chr10-87933252-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 404166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.492+2del		splice_donor_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.1011+2del		splice_donor_variant
PTEN	NM_001304718.2	c.-258+2del		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.492+2del		splice_donor_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 09, 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. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 33887726, 33876391, 28677221, 24345843, 32196895, 21659347]. -

PTEN hamartoma tumor syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 29, 2023

This sequence change affects a splice site in intron 5 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 eosinophilic gastrointestinal disorder and PTEN hamartoma tumor syndrome (PHTS) (PMID: 21659347, 24345843). ClinVar contains an entry for this variant (Variation ID: 404166). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs1060500124; hg19: chr10-89693009; COSMIC: COSV64288576;