10-87931094-G-T

Variant names:

• chr10-87931094-G-T
• rs1554897889
• NM_000314.8:c.253+5G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000314.8(PTEN):​c.253+5G>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.32

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-87931094-G-T is Pathogenic according to our data. Variant chr10-87931094-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87931094-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.253+5G>T		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.772+5G>T		splice_region_variant, intron_variant	Intron 5 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.-498+5G>T		splice_region_variant, intron_variant	Intron 3 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.253+5G>T		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Sep 26, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data, PMID: 28677221]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24375884 ,28677221]. -

May 26, 2017

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2

Dec 12, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Non-canonical splice site variant demonstrated to cause exon skipping and predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Chen et al., 2017); Observed in individuals with personal and/or family history consistent with PTEN hamartoma tumor syndrome (PHTS) referred for genetic testing at GeneDx and in published literature (Chen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28677221, 24375884) -

Nov 18, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported in individuals affected with Cowden syndrome and macrocephaly in the published literature (PMIDs: 24375884 (2014) and 28677221 (2017)). One cell-based study reports this variant results in skipping of exon 4 in the PTEN gene which is predicted to result in a frameshift (p.Ala72Thrfs*5), and is damaging to PTEN protein expression (PMID: 28677221 (2017)). Therefore, the variant is classified as pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 28677221). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 427617). This variant has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PHTS) (PMID: 24375884, 28677221; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253+5G>T intronic pathogenic mutation results from a G to T substitution 5 nucleotides after coding exon 4 in the PTEN gene. This nucleotide position is highly conserved in available vertebrate species. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with PTEN hamartoma tumor syndrome (Vanderver A et al. Am J Med Genet A, 2014 Mar;164A:627-33). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in out of frame exon 4 skipping in the set of samples tested (Chen HJ et al. Hum Mutat, 2017 Oct;38:1372-1377, Ambry internal data). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554897889; hg19: chr10-89690851; COSMIC: COSV64298366;